Program Schedule

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Keynote Speaker

Time:

Title: Multimodal magnetic resonance and Near-Infrared-Fluorescent imaging of intraperitoneal ovarian cancer using a Dual-Mode-Dual-Gadolinium liposomal contrast agent

Vikas Kundra
M.D. Anderson Cancer Center, USA

Biography

Vikas Kundra is Professor and Director of Molecular Imaging in the Department of Radiology, U.T.- M.D. Anderson Cancer Center with joint appointment in the Department of Cancer Systems Imaging. He received his M.D. and Ph.D. from Harvard University and completed his radiology training at Brigham and Women’s Hospital. He is a Fellow of the Society of Body Computed Tomography-Magnetic Resonance Imaging and a Distinguished Investigator of the Academy of Radiology Research. Clinical work focuses on Body Imaging particularly in cancer and research focuses on molecular imaging, including imaging of gene expression and nanotechnology.

Abstract

The degree of cytoreduction at surgery is one of the most important prognostic factors for ovarian cancer. A multimodality agent that can be used with magnetic resonance (MR) for staging and pre-surgical planning, and with optical imaging to aid surgical removal of tumors, would present a new paradigm for ovarian cancer. We assessed whether a dual-mode, dual-Gadolinium (DM-Dual Gd-ICG) contrast agent can be used to visualize intraperitoneal ovarian tumors by multimodal MR and near infra-red (NIR) imaging. Intraperitoneal ovarian tumors (Hey-A8 or OVCAR3) in mice enhanced on MR two days after intravenous DM-Dual Gd-ICG injection compared to controls. As seen on open abdomen and excised tumors views and confirmed by radiant efficiency measurement, Hey-A8 or OVCAR3 tumors from animals injected with DM-Dual Gd-ICG had increased NIR fluorescence. As controls, increased MR signal was not seen by Gd-chelate alone nor was increased NIR signal seen by ICG alone 2 days after injection at doses similar to those given by DM-Dual Gd-ICG. This suggests clinical potential to localize ovarian tumors by MR for staging and surgical planning, and, by NIR at surgery for resection.

Keynote Speaker

Time:

Title: Osteopontin splice variants in cancer dissemination

Georg F. Weber
University of Cincinnati, USA

Biography

Georg F. Weber attended medical school in Würzburg, Germany. He worked at the Dana-Farber Cancer Institute, Harvard Medical School from 1990 through 1999 and is currently on the faculty at the University of Cincinnati. Georg F. Weber has published about 90 scientific reports, including many in the most respected professional journals, as well as various monographs, including textbooks on molecular oncology and anti-cancer drugs. He holds several U.S. and international patents.

Abstract

In cancer, metastases manifest clinically at advanced disease stages. The dissemination of the transformed cells is an integral characteristic of malignancies and is absent from benign growths. While the major limiting factor in cancer spread is the death of the tumor cells before their implantation into target organs, a fraction of the released cells can survive in the circulation for extended periods of time. The molecular programs of metastasis act to promote tumor progression, not growth or extension of life span. Besides inducing directed migration and invasion, they support adhesion-independent survival. The cytokine Osteopontin is a metastasis gene product that supports the progression of over 30 aggressive tumors. The protein exists in three splice variants, dubbed Osteopontin-a (full-length), -b (lacking exon 5), and -c (lacking exon 4). 1) Untransformed non-hematopoietic cells undergo programmed cell deathconsecutive to losing contact with their substratum. Anchorage-deprivation causes impairment in glucose transport, a deficit in ATP availability and consecutiveanoikis. In cancer cells that have been shed from the primary tumor, metastasis gene products support enhanced energy generation and survival. Variant forms of Osteopontin act as autocrine inducers. Osteopontin-a increases the levels of glucose in deadherentbreast cancer cells. Osteopontin-c, upregulates peroxides as well as intermediates of the hexose monophosphate shunt and glycolysis, which utilize the available glucose and can feed into the tricarboxylic acid cycle. Consecutively, the cellular ATP levels are elevated and the cells can survive. 2) Osteopontin-c is present in 75-80% of breast cancers and 0% of normal breast tissues. It increases with tumor grade. In early breast cancer, high staining intensity of nuclear Osteopontin-c is strongly associated with mortality. Osteopontin-c is not correlated with proliferation markers, ER, PR, or HER2. Bya real-time RT-PCR test,the elevation in Osteopontin-c in the blood detectsa fraction of breast cancers, suggesting prognostic potential of a blood test. Cytosolic staining for exon 4, reflective of Osteopontin-a and -b also predicts poor outcome.In therapy responses, exon 4 is associated with a favorable response to tamoxifen, but a poor response to chemotherapy with CMF (cyclophosphamide, methotrexate, fluorouracil). Osteopontin-c falls short of being a significant predictor for sensitivity to the treatments investigated. The addition of Osteopontin splice variant immunohistochemistry to standard pathology work-ups has the potential to aid decision making in breast cancer treatment. Acknowledgement: This research was supported by U.S. DOD grant BC095225 and the Marlene Harris-Ride Cincinnati/Pilot Program.

Keynote Speaker

Time:

Title: Oncogenic activity of fusion genes

Jianhua Luo
University of Pittsburgh School of Medicine, USA

Biography

Dr. Luo been studying molecular pathology related to human malignancies in the last 24 years. Currently, he is a Professor of Pathology and Director of High Throughput Genome Center at University of Pittsburgh. In the last 16 years, Dr. Luo has been largely focusing on genetic and molecular mechanism of human prostate and hepatocellular carcinomas. In this period, his group has identified and characterized several genes that are related to prostate cancer and hepatocellular carcinoma, including SAPC, myopodin, CSR1, GPx3, ITGA7, MCM7, MT1h and GPC3. He has characterized several signaling pathways that play critical role in prostate cancer development, including Myopodin-ILK-MCM7 inhibitory signaling, myopodin-zyxin motility inhibition pathway, CSR1-CPSF3, CSR1-SF3A3 and CSR1-XIAP apoptotic pathways, MT1h-EHMT1 egigenomic signaling, ITGA7-HtrA2 tumor suppression pathway, GPx3-PIG3 cell death pathway, AR-MCM7 and MCM7-SF3B3 oncogenic pathways. He proposed prostate cancer field effect in 2002. He is one of the pioneers in utilizing high throughput gene expression and genome analyses to analyze field effects in prostate cancer and liver cancer. He is also the first in using methylation array and whole genome methylation sequencing to analyze prostate cancer. Recently, Dr. Luo’s group found that patterns of copy number variants of certain specific genome loci are predictive of prostate cancer clinical outcomes, regardless tissue origin. His discovery of several novel fusion transcripts and their association with aggressive prostate cancer has brought significant new insight into the field of prostate cancer research. Overall, these findings advance our understanding onhow cancer develops and behaves, and lay down the foundation for better future diagnosis and treatment of human malignancies.

Abstract

Accurate prediction of prostate cancer clinical courses remains elusive. In recent studies, we performed whole genome analysis on prostate cancers by combiningAffymetrix SNP6.0 chip, whole genome sequencing and transcriptome sequencing. Our result showed that combination of genome copy number variance and novel fusion transcripts specific for cancer achieved high accuracy in predicting prostate cancer outcomes. The prediction model was further improved when these molecular criteria were combined with Nomogram or Gleason’s grading. Interestingly, some of these fusion genes are also present in a variety of human malignancies. Treatment of cancers with drugs specific for fusion gene signaling pathways produced dramatic improvement of metastasis and survival rate of animals xenografted with cancers positive for fusion genes. Our analyses suggest that targeting therapy for fusion genes holds promise as an effective treatment for human cancers.

Keynote Speaker

Time:

Title: Role of Human Papillomavirus type-16 infection for various cancers as well as Alzheimer’s disease and Autism, and safe, effective treatment of cancer by the combined use of optimal doses of Vitamin D3, Taurine, & PQQ when they are positively synergetic with additional advantage of significant urinary excretion of HPV-16 Virus and other bacterial and fungal infections

Yoshiaki Omura
New York Medical College, USA

Biography

Yoshiaki Omura received Oncological Residency training at Cancer Institute of Columbia University & Doctor of Science Degree through research on Pharmaco-Electro-Physiology of Single Cardiac Cells in-vivo and in-vitro from Columbia Uni.. He researched EMF Resonance phenomenon between 2 identical molecules for non-invasive detection of molecules, at Graduate Experimental Physics Dept., Columbia Uni., for which he received U.S. patent. He is also the creator of Bi-Digital O-Ring Test. He published over 270 original research articles, many chapters, & 9 books. He is currently Adjunct Prof. of Family & Community Medicine, New York Medical College; President & Prof. of Int’l College of Acupuncture & Electro-Therapeutics, NY; Editor in Chief, Acupuncture & Electro-Therapeutics Research, Int’l Journal of Integrative Medicine, (indexed by 17 major int’l Indexing Periodicals); Formerly, he was also Adjunct Prof. or Visiting Prof. in Universities in USA, France, Italy, Ukraine, Japan, Korea, & China.

Abstract

A previous analysis of 500 breast cancer patients’ mammograms indicated that more than 90 percent of breast cancer tissue has human papillomavirus type-16 (HPV-16). Type-18 was found in less than a few percent. Human papillomavirus was measured non-invasively and rapidly using strong Electromagnetic Field (EMF) Resonance phenomenon between 2 identical substances with the same weight, for which US patent was given in 1993. Because of these findings, the relationship between HPV-16 and various cancers was studied. In various cancers including brain tumors, a significant infection of HPV-16 was detected in every cancer tissue evaluated. HPV-16 was found to be highly infectious, particularly when oral cavities have HPV-16 infection of more than 2000ng BDORT Units. In families where one member has a strong infection of HPV-16, other members of the family often have the same degree of infection. When one has a strong HPV-16 infection, there is a high tendency of developing cancers at the most infected organ. Even if the patient does not develop malignancies, when a strong infection of HPV-16 virus is present, β-amyloid (1-42), which is increased in Alzheimer’s disease and autism, is also increased in the infected area of the body. When this is increased in cancer tissue, we found naturally existing molecules Vitamin D3 & its derivatives, Taurine (sulfur containing one type of amino acid) and PQQ were often reduced in the cancer tissue or infected areas. Therefore, we give these naturally existing substances, namely optimal doses of Vitamin D3 (400 I.U.), Taurine (~175mg), and PQQ (5-10mg). When these 3 substances are independently used, an optimal dose produces very significant anti-cancer effects and increases Acetylcholine and DHEA levels. In addition, viruses such as HPV-16 & CMV, bacteria such as Lyme Borrelia Burgdorferi spirochaete, & fungi like Candida Albicansare excreted through urine in very significant amounts. These effects are even more beneficial when used in a compatible combination of all 3, particularly when a compatible dose of Cilantro tablets is used together. We also found many atrial fibrillations are due to Lyme Burgdorferi infection of SA node and atrium areas. These infections can be effectively reduced without using anti-viral or anti-bacterial agents, but by simply using combination of compatible optimal doses of Vitamin D3, Taurine, and PQQ. Cancer is potentially transmitted by HPV-16 infection. The best treatment of cancer should have not only inhibition of cancer activities, but also simultaneous elimination of the viral infection using optimal doses of these naturalcomponents of our body mentioned, although other overdosed supplements (Vit. C, etc.) or certain medications can inhibit these beneficial effects. In order to give the best treatment combination, optimal doses and selection of combinations must be determined individually and prevent potential drug interactions with other medications or supplements.

Sessions:
Cancer Care and Psychological Support & Cancer Etiology and Epidemiology

Time:

Title: Psychosocial risk factors for cancer diseases: The case of breast cancer in adults, and the case of leukemia in children and teens

Shulamith Kreitler
Tel-Aviv University, Israel

Biography

Shulamith Kreitler was born in Tel-Aviv, has studied psychology, philosophy and psychopathology in Israel, Switzerland and the USA. She got her PhD in BernSwitzerland. Has worked as a professor of psychology in different universities, including Harvard, Princeton and Yale in the USA, as well as in Argentina and Vienna, Austria. She has been a full professor of psychology at Tel-Aviv University since 1986. She is a certified clinical and health psychologist. She is the head of the psychooncology research center at ShebaMedicalCenter. Has published about 200 papers and 10 books in motivation, cognition, psychopathology and health psychology. She has created the theory of meaning, the cognitive orientation theory of behavior and wellness, and an innovative approach to psychological risk factors of physical disorders. Some of her publications: The Psychology of Art (1972), Cognitive Orientation and Behavior (1976), The Cognitive Foundations of Personality Traits (1990), Handbook of Chronic Pain (2007), Pediatric Psycho-Oncology: Psychosocial Aspects and Clinical Interventions (2004, 20122nd Edition), Cognition and Motivation (2012).

Abstract

Assessed psychological tendencies and attitudes identified in pretest Previous studies about psychosocial correlates of cancer patients led to inconclusive results Studies by Kreitler et al. (2002) showed that focusing on theoretically-relevant factors provides new insights into psychosocial correlates of cancer patients that have the potential of being shown to be risk factors for cancer. This approach is grounded in the Cognitive Orientation (CO) theory of health behavior and wellness which enables identifying relevant factors in cancer patients. The major constructs of this theory are beliefs of four types (about oneself, reality, goals and norms) that refer to specific themes representing underlying meanings identified by a procedure of targeted interviewing in pretest subjects. The utility of the CO approach has been proven in regard to colorectal cancer. The goal of the present talk is to examine whether psychosocial correlates grounded in the CO theory can be identified in adult breast cancer patients (Study 1) and in pediatric leukemia patients (Study 2). On the basis of previous findings it was expected that characteristic themes will be identified in each group and that they would differ in the two groups. Study 1: The participants were250 breast cancer patients and 180 matched healthy controls. They were administered the CO questionnaire assessing psychosocial tendencies and attitudes identified in pretests as relevant for breast cancer. Discriminant and logistic regression analyses showed that patients and controls differed significantly in most of the assessed variables (belief types and themes), referring to themes, such as concern with controlling oneself and others, dependence on others’ evaluations, emotional blocking, and conflicts about self identity and giving to others. Some of these variables were related to medical features, none to demographic ones. Study 2: The participants were 32 pediatric patients with leukemia (AML, CML), 27 pediatric cancer patients with solid tumors, and 30 healthy controls (age 5-10). The CO questionnaire they were administered assessed psychological tendencies and attitudes identified in pretests with children with leukemia. Analyses of variance and discriminant analyses showed significant differences between the three groups. The major discriminating themes referred to needs for freedom, routine, pleasing others, and avoidance of criticism. Conclusions: The CO theory and methodology enable identifying sets of psychological correlates characteristic for different cancer diseases in both adults and children. These correlates have the potential of being psychological risk factors for the different diseases and could serve as basis for adjuvant psychological interventions.

Time:

Title: Giant obscurins act upstream of the PI3K/Akt pathway in breast epithelial cells

Aikaterini Kontrogianni-Konstantopoulos
University of Maryland School of Medicine, USA

Biography

Aikaterini Kontrogianni-Konstantopoulos received her Ph.D. from the Department of Cell Biology at Baylor College of Medicine in Houston, TX. After graduating from Baylor, she joined the laboratory of Dr. E.J. Benz, Jr., in the Division of Hematology, at Johns Hopkins University, School of Medicine as a post-doctoral fellow. In 2007, she joined the Department of Biochemistry and Molecular Biology in the University of Maryland School of Medicine as Assistant Professor, and in 2012 was promoted to Associated Professor. Her research focuses on the elucidation of the roles of cytoskeletal and membrane-associated proteins as structural and signaling mediators. Using the muscle and epithelial cell as model systems, my laboratory has pioneered the molecular and functional characterization of the obscurin subfamily and its binding partner Myosin Binding Protein-C slow in health and disease. Her research has been funded by several organizations, including NIH, Muscular Dystrophy Association and American Heart Association.

Abstract

Obscurins, encoded by the single OBSCN gene, are giant cytoskeletal proteins containing tandem adhesion and signaling domains. The OBSCN geneis highly mutated in multiple types of cancer, including breast cancer, resulting in a 2-fold reduction of its mRNA levels. Consistent with this, obscurin proteins are nearly lost from human breast cancer cell lines and advanced stage biopsies, independently of their hormonal status or molecular differentiation. Loss of giant obscurins from breast epithelial cells confers them with a survival and growth advantage following exposure to common chemotherapies. Obscurin-depleted breast epithelial cells fail to form adhesion junctions, undergo epithelial-to-mesenchymaltransition (EMT),and generate primary and secondary mammospheres bearing markers of cancer-initiating cells. Moreover, obscurin-deficient breast epithelial cells display markedly increased motility as a sheet in 2-dimensional (2D) substrata and individually in confined spaces, and increased invasion in3D matrices. They are also capable ofextending microtentacles mediating the attachment of circulating tumor cells to the endothelium, an advantage that persists even after paclitaxel treatment. More importantly, loss of giant obscurins from breast epithelial cells promotes primary tumor formation and lung colonization in vivo.These major phenotypic alterations appear to be the result,at least in part ofincreased PI3K activity, a key regulator of tumorigenesis and metastasis. Pharmacological and molecular inhibition of the PI3K/Akt pathway in obscurin-depletedbreast epithelial cells results in reversal of EMT, (re)formation of cell-cell junctions,diminished mammosphere formation, and decreased cell migration and invasion. Coimmunoprecipitation,pull-down, and surface plasmon resonance assays revealedthat obscurins are in a complex with the PI3K/p85 regulatory subunit, and that theirassociation is direct and mediated by the obscurin-PH domain and the PI3K/p85-SH3domain with a KD of ~50 nM. We therefore postulate that giant obscurins act upstreamof the PI3K/Akt cascade in normal breast epithelial cells, regulating its activation throughbinding to the PI3K/p85 regulatory subunit.

Time:

Title: The possible involvement of Epstein–Barr Virus in the etiology of leukemia in Sudanese patients

Haitham E Elawad
Omdurman Islamic University, Sudan

Biography

Dr. Haitham Eltigani Mohammed Alawad is currently serving as an assistant professor in virology and immunology. He is the Executive editor of Sudan medical laboratory Journal (SMLJ).

Abstract

The research studies the etiology of Leukemia. No single known cause for all of the different types of leukemia exists. Controversial hypotheses was proposed suggesting the role of physical as well as chemical and even biological factors as being responsible for Leukemia incidents. The actual cause of Leukemia which is a serious cancer in Sudan is still under scrutiny. We hypothesized that EBV could be involved in the etiology of leukemia. We describe here the results of our attempt to find a possible link between leukemia and EBV. It is generally accepted that the (EBV) is an important etiologic factor in various tumors. Virtually little was reported about the relationship between EBV genes and leukemia. However, no full-length analysis of any substrain of EBV in Sudan area has been reported. The main objective of this study is to assess the incidence and the significance of EBV in patients with leukemia disorder using diagnostic parameters including cell Morphology, immunologic markers, and molecular investigations. Our findings provided evidence of the involvement of EBV in patients with leukemia. The results suggested that EBV DNA genome encoding the non-glycosylated membrane protein BNRF1 pl43 was observed in a significant proportion of patients with ALL. We could not exclude a correlation between these viral infections and later leukemogenesis in childhood ALL in Sudan. Further investigation on the link between maternal EBV reactivation and the development of ALL in offspring needs to be explored. Neither latent infection nor congenital infection could be excluded.

Time:

Title: Patterns of cancer incidence in Eastern Ethiopia compared with other countries world wide and used to identify for a potential environmental carcinogen based on detail demographic studies of the patients

Getamesay Kebede
Dire Dawa and Haromaya University, Ethiopia

Biography

Getamesay Kebede is an Assistant Professor of Clinical Pathology has been working professionally since 2010 at Haromaya University, Ethiopia. He is energetic and enthusiastic on his work and researches. He has written a paper on breast cancer and has ongoing studies on tuberculosis and on infant mortality. Getamesay received his doctorate degree in medicine at Gondar University in Gondar, Ethiopia and speciality in Clinical Pathology at Addis Ababa University, Ethiopia.

Abstract

In order to know the Epidemiology of cancer in Eastern Ethiopia datas from pathology departments of Dilchora Hospital and HiwotFana Hospital were analysed. Data from Dilchora Hospital was collected for 128 cancer cases diagnosed during the year 2015 G.C. Results on the cancer incidence by site and sex for the region was - for women the three most common malignancies in descending order of frequency are breast cancer (27.3%), hematologic malignancies (16.7%), and soft tissue sarcoma (15.2). The figure in men in descending order of frequency is GI malignancies (18%), hematologic malignancies (17.5) and secondaries of carcinomas in cervical lymphnodes (16%). GI malignancies are more prevalent in males (18%) than in females (6%). Hematologic malignancies showed equal number of cases in either sexes (n=11). The life style of men in the region like khat chewing, chronic alcoholism and cigarrete smoking seem to contribute to the higher incidence of GI malignancies and secondaries of carcinoma in the cervical lymphnodes. The comparable risk of developing hematologic malignancies in both sexes may stem from a common environmental carcinogen which needs further intensive study.

Sessions:
Diagnostic Methods for Cancer Treatment

Time:

Title: The presence of breast cancer related proteins in saliva

Charles F. Streckfus
University of Texas, USA

Biography

Dr. Charles F. Streckfus is currently a professor in the Department of Diagnostic & Biomedical Sciences at the University of Texas School of Dentistry at Houston and formerly the Assistant Dean of Research at the University of Mississippi Medical center Dental School. He received his Bachelor of Science degree in Biology from Johns Hopkins University and he graduated with a DDS degree from the University of Maryland School of Dentistry. Dr Streckfus was a senior post-doctoral fellow at NIDCR and P.I. of the Oral Physiology component of the Baltimore Longitudinal Study on Aging. Dr. Streckfus has over 100 peer-reviewed journal articles and has been invited to speak at numerous national and international conferences. He has received many honors and awards which include the prestigious President’s Award for Scientific Excellence, Presented by the International Society for Preventive Oncology, awarded at the Pasteur Institute, Paris, France, the NIH Award of Merit for his statistical analysis of the NHANES III Study, the ADA recognition award for services on the Council of Scientific Affairs, the American Academy of Oral Medicine Service Award and the Mayor of Baltimore City Baltimore’s Best Award for rendering dental services to the underserved citizens of Baltimore. He was granted 4 patents for his work in breast cancer biomarker research all which were assigned to the University of Mississippi Medical Center and the University of Texas Health Science Center.

Abstract

The objective of this presentation is to introduce a catalogue of salivary proteins that are altered secondary to carcinoma of the breast. The catalogue of salivary proteins is a compilation of twenty years of research by the author and consists of 233 high and low abundant proteins which have been identified by LC-MS/MS mass spectrometry, 2D-gel analysis and by enzyme-linked immunosorbent assay. Many of the identified proteins are present in the majority of cancer related pathways. Consequently, the body of this research suggests that saliva is a fluid suffused with solubilized by-products of oncogenic expression and that these proteins may be useful in the study of breast cancer progress, treatment efficacy and the tailoring of individualized patient care.

Time:

Title: Is molecular breast imaging an appropriate modality for breast cancer screening?

Tanya W. Moseley
The University of Texas MD Anderson Cancer Center, USA

Biography

Tanya W. Moseley, MD has distinguished herself as an outstanding breast radiologist, clinician, and educator. Dr. Moseley received her Doctorate of Medicine with Honors at the University of Iowa College of Medicine in Iowa City, Iowa. She entered a Clinical Residency in Diagnostic Radiology at the Mayo Clinic Graduate School of Medicine in Rochester, Minnesota, and continued on at the Mayo Clinic in a Clinical Fellowship in Mammography and Thoracic Imaging. After completing her fellowship, Dr. Moseley joined Mayo Clinic as a Senior Associate Consultant, and then joinedthe Division of Diagnostic Imaging at MD Anderson Cancer Center in 2001. She serves the institution as a Professor of Diagnostic Imaging.

Abstract

Less than 20 years ago the only weapons in the arsenal of breast oncologists were chemotherapy and tamoxifen. Today there are many molecules that can potentially target the known oncogenes. The discovery of HER2 and the development of trastuzumab pioneered the field of targeted therapy in breast cancer. Breast imagers partner with their oncology colleagues to screen for breast cancer and to evaluate response to therapy. Although mammography, breast ultrasound, and breast MRI are excellent imaging tools, molecular breast imaging (MBI) has the potential to become a screening modality.

Time:

Title: Systematic analysis of liver cancer metabolism - lessons from mice and humans

Stefan Kempa
Berlin Institute for Medical Systems Biology at the MDC Berlin, Germany

Biography

Stefan Kempa is group leader at the Berlin Institute for Medical Systems Biology BIMSB at the Max Delbruck Center for Molecular Medicine in Berlin, Germany. The group established gas chromatography coupled mass spectrometry (GC-MS) as well as liquid chromatography coupled mass spectrometry (LC-MS) based techniques to monitor the metabolome and the proteome. In addition they have developed pulsed stable isotope resolved metabolomics (pSIRM) as a tool for a dynamic metabolic characterization of cellular metabolism. Using this technology they investigate cancer metabolism aiming to improve the understanding of cancer. The specific interest is to understand metabolic dependencies of cancer cells and to improve cancer treatment.

Abstract

Metabolic reprogramming is a required step during oncogenesis. It is triggered by activation of oncogenes and loss of tumor suppressors and leads to an activation of central metabolic pathways to support cell growth and proliferation. In order to quantify the usage and activity of metabolic pathways in vitro and in vivo we have developed pulsed stable isotope resolved metabolomics (pSIRM). The applied GC-MS based technology enables the absolute quantification of metabolites and at the same time the determination of stable isotope incorporation. Using pSIRM we have characterized the action of inhibitors of glycolysis in cell cultures. We observed that the commonly used compound 2-deoxyglucose is not a specific glycolytic inhibitor, the action of 3-bromopyruvate as glycolytic inhibitor could be confirmed. We next analyzed the metabolic program of hepatocellular carcinoma using quantitative proteomics and in vivo isotope labelling. We further characterized the action of glycolytic inhibitors in a HCC-mouse model. Finally, we compared the metabolic phenotype of HCC between mice and humans. And observed striking similarities at the metabolic level.

Time:

Title: Magnetic resonance metabolic analysis provides targets for suitable drugs and biomarkers for prognosis to targeted signaling inhibitorson cancer

Seung-Cheol Lee
University of Pennsylvania, USA

Biography

Dr. Lee is a research assistant professor of the department of radiology, University of Philadelphia.He obtained PhD from department of physics, KAIST, Korea and had postdoc training in in vivo NMR of cells and tumors from Korea Basic Science Institute and University of Pennsylvania. His research focus is NMR/MRI based metabolic investigation of cancer in cells, animal models and human patients for the purpose of detecting early therapeutic response to novel targeted drugs. He is a recipient of ACS-IRG, ITMAT and McGaberesearch funds.

Abstract

We are exploring metabolic information obtainable from nuclear magnetic resonance (NMR) and mass spectrometry (MS) to correlate cellular and tumor response to targeted signaling inhibitors. 13C NMR and MS of mantle cell lymphoma cells after incubation with13C-labeled glucose or glutamine provided isotope enrichment of several key metabolites. The enrichment information was converted to metabolic fluxes including glycolysis, pentose phosphate pathway, TCA cycle, glutaminolysis and de novo fatty acids synthesis, by using a novel bonded cumomer metabolic flux analysis. The alteration in metabolic fluxes following signaling inhibitors correlated with changes in associated gene expression as analyzed from RNA sequencing data. There was a four-fold decrease in glycolysis in RL cells vs a two-fold decrease in Jeko cells after same amount of ibrutinib, a Bruton tyrosine kinase inhibitor. Also, there was a two-fold decrease in glutaminolysis in RL cells while no change in Jeko cells. De novofatty acids productiondecreased by two-fold in RL cells vs no change in Jeko cells. The results suggest metabolic targets of additional drugs for ibrutinib-resistant Jeko cells. The glucose uptake decreased similarly in both RL and Jeko cells after ibrutinib while there was a two-fold difference in lactate production change between RL and Jeko cells. This result suggests lactate as a promising marker of the tumor response to this signaling inhibitor. It is particularly significant because FDG-PET has been failing to distinguish responding patients from non-responding patients at interim scans during treatment. We have developed a novel 1H magnetic resonance spectroscopy (MRS) lactate imaging technique for cancer patients and pursuing its application to detecting response to signaling inhibitor therapy in lymphoma patients.

Time:

Title: A prospective study of chemo-predictive assay for targeting cancer stem cells in Glioblastoma patients

Pier Paolo Claudio
University of Mississippi, USA

Biography

Dr. Claudio completed his medical and graduate training at the University “Federico II” in Naples, Italy. He then completed two postdoctoral fellowships in molecular biology and cancer biology at Temple University and at Jefferson University in Philadelphia, USA. In 2006 he moved at Marshall University in West Virginia where he became tenured Associate Professor in the Department of Biochemistry and Microbiology and director of the Translational Laboratories at the Translational Genomic Research Institute, Edwards Comprehensive Cancer Center. There he developed the ChemoID®drug response assay, which compares the sensitivity of cancer stem cells vs. bulk of tumor cells to chemotherapy. Three international patents cover the ChemoID®procedure, which is a second-generation functional drug response assay that uses a patient’s live tumor cells to indicate which chemotherapy agent (or "combinations") will kill the bulk of the cancer tumor and the cancer stem cells (CSCs) that are known to cause cancer to recur. In 2010 he co-founded Cordgenics, LLC a US company that is focused on cancer stem cells diagnostics and discovery of novel therapeutics. He moved to the University of Mississippi in 2015 as tenured Professor in the Department of BioMolecular Sciences, National Center for Natural Products Research (NCNPR), and Department of Radiation Oncology, where he became the Director of the Translational Laboratories at the Medical Center Cancer Institute. Dr. Claudio has authored 143 publications in biomedical journals to date. He has served or serves on numerous grant review panels for NIH, NCI, DOD, and foreign research funding agencies from Italy, Germany, The Netherlands, Neurasia, and the European Commission. He serves as Editor or Associate Editor of a number of biomedical journals, and has served as an advisor to several pharmaceutical and biotechnology companies.

Abstract

Introduction. Prognosis of glioblastoma (GBM) treated with standard-of-care maximal surgical resection and concurrent adjuvant temozolomide (TMZ)/radiotherapy is still very poor (median survival =14.2 months).It has been observed that glioblastomas contain a small population of cancer stem cells (CSCs) that contribute to tumor propagation, maintenance, and treatment resistance. Administration of ineffective anticancer therapy is associated with unnecessary toxicity and development of resistant cancer cell clones. We have developed a drug sensitivity assay (ChemoID) that identifies the most effective chemotherapy management against CSCs and bulk of tumor cells offering great promise for individualized anticancer treatments. A prospective study was conducted evaluating the use of the ChemoID drug sensitivity assay in glioblastoma patients treated with standard-of-care. Methods. 30 glioblastoma patients, 18-years and older, male/females, eligible for a surgical biopsy, were enrolled in an IRB-approved protocol, and fresh tissue samples were collected for drug sensitivity testing. All patients were treated with standard-of-care TMZ plus radiation with or without maximal surgery, depending on the status of the disease. Each treatment was classified by the assay as: sensitive (S = >60% cell kill), intermediate (I= 30-60% cell kill), or resistant (R= <30 cell kill). Patients were prospectively monitored for tumor response, time to recurrence, progression-free survival (PFS), and overall survival (OS). Associations of assay response for the standard-of-care TMZ selected treatment with tumor response, time to recurrence, PFS, and OS were analyzed. Results. The median follow-up analysis was 8 months (3-49 months). ChemoID assay on CSCs demonstrated a sensitivity of 100% and a specificity of 95.83%, with a positive predictive value of 80%, and a negative predictive value of 100%. The ChemoID assay on bulk of tumor demonstrated instead a sensitivity of 100% and a specificity of 87.50%, with a positive predictive value of 57.14%, and a negative predictive value of 100%. Overall, patients treated with assay-sensitive or -intermediate (S+I) TMZ against CSCs demonstrated significantly improved tumor response withincreased medianand mean time to recurrence, improved median PFS, and prolonged mean OS,when compared to patients treated with assay-resistant TMZ to CSCs or with assay-sensitive or –intermediate TMZ to bulk of tumor cells. Conclusions.This prospective study compared the sensitivity of patient derived GBM CSCs and bulk of tumor cells to variouschemotherapies, demonstrating that GBM patients treated with TMZwhose CSCs were found sensitive (S+I) to TMZ, experienced improved tumor response; extended mean and median time to recurrence; improved median PFS, and prolonged mean OS.

Time:

Title: Capturing dissociated cells from core needle biopsies: Up front triaging to enhance comprehensive diagnostics

Wilfrido D. Mojica
University at Buffalo, USA

Biography

Dr. Mojica is a practicing surgical pathologist and Assistant Clinical Professor with the Department of Pathology and Anatomical Sciences at the University at Buffalo. He completed his MD degree from the St. Louis University School of Medicine and is trained and board certified in both Anatomic and Clinical Pathology. He heads the immunohistochemistry section within the Kaleida Health Laboratory. He has published over 30 peer review manuscripts related to translational research and pathologic biospecimens.

Abstract

Dr. Mojica is a practicing surgical pathologist and Assistant Clinical Professor with the Department of Pathology and Anatomical Sciences at the University at Buffalo. He completed his MD degree from the St. Louis University School of Medicine and is trained and board certified in both Anatomic and Clinical Pathology. He heads the immunohistochemistry section within the Kaleida Health Laboratory. He has published over 30 peer review manuscripts related to translational research and pathologic biospecimens.

Sessions:
Organ Specific Cancers and Effects & Radiation, Surgical and Medical oncology

Time:

Title: p65BTK is a novel therapeutic target in p53-null drug-resistant colon cancers

Emanuela Grassilli
University of Milano-Bicocca, Italy

Biography

Dr. Grassilli received her Ph.D. degree from the University of Modena, Italy, and pursued her post-doctoral research at Thomas Jefferson University, Philadelphia and European Institute of Oncology, Milan, Italy studying the molecular mechanisms of apoptosis and their relevance in the response to chemotherapy. More recently, she co-founded Bionsil, a spin-off of the University of Milano-Bicocca, Italy, aimed at identifying and characterizing novel targets for molecular diagnosis and therapy of drug-resistant cancers. From 2014 she is Assistant Professor at the University of Milano-Bicocca where she continues her work on p65BTK, a novel Bruton’s Tyrosine isoform previously identified as a new target of therapy in colon cancers.

Abstract

We recently identified p65BTK, a novel oncogenic isoform of Bruton tyrosine kinase abundantly expressed in colon cancer cell lines and tissues (Grassilli et al, Oncogene 2016) and showed that its inhibition affects growth and survival of colon cancer cells. Here we report that p65BTK expression significantlyincreases with the stage and the grade of colon carcinoma and correlates with cancer progression. In addition, p65BTK is strongly expressed in organoidsderived from stem cells purified from patients’ colon cancer tissues and in cancer stem cellsisolated from colon cancer specimens. In vitro, p65BTK silencing (by siRNA or shRNA) and its inhibition by different specific inhibitors (Ibrutinib, AVL-292, RN486) sensitize drug-resistant p53-null colon cells and patient-derived organoidsto 5FU. At variance, blocking p65BTK does not restore the response of resistant cells to anti-EGFR receptor antibodies (panitumumab, cetuximab) and inhibitors (afatinib, poziotinib) or to bevacizumab. Conversely, p65BTK overexpression (but not overexpression of a kinase-dead mutant) protects p53-wt colon cancer cells from 5FU-induced cytotoxicity. Accordingly, p65BTK inhibition restores the apoptotic response to 5FU of drug-resistant p53-null colon cancer cellsvia imbalancing the anti-/pro-apoptotic ratio of Bcl-2 family members. In particular, p65BTK inhibition blunts 5FU-stimulated induction of the TGF- pathway (anti-apoptotic) and induces E2F-mediated transcriptional regulation (apoptotic). Finally, in xenograft experiments we confirmed that the combinationof 5FU with a BTK inhibitor (Ibrutinib) significantly reduced tumor volume in mice compared to the use of 5FU alone. In conclusion, our data indicate that p65BTK targeting restores the apoptotic response to chemotherapy of p53-null drug-resistant colon cancer cells and suggest that the addition of BTK inhibitors to classic chemotherapy may represent a novel approach to bypass drug resistance.

Time:

Title: Cytotoxic activity of fractions Stenocereus griseus H on HeLa cell lines

Rafael Silva Torres
Instituto Politecnico Nacional, Mexico

Biography

Rafael Silva Torres has completed his PhD. from EscuelaNacional de CienciasBiológica of National Polytechnic Institute and abroad studies M. Phil. from Loughborough University of Technology Great Britain and sabbatical year from Museum National D`HistoireNaturelle Paris France. He has published more than 15 papers in reputed journals and 4 book chapters and has been serving as editorial board member of repute journals. He was director of 49 Bsc. Thesis and he was participated in more than 150 national and international congresses. He is membership of National Association of Pharmaceutical Sciences and American Chemical Society. He is investigating the properties antitumor of medicinal plants such as: Sedum praealtumDC.,Sechiumedule and Stenocereusgriseus H

Abstract

Cervical cancer is the largest cancer incidence in Mexico and is the leading cause of cancer death among Mexican women. Risk factors involve early onset of sex, having multiple sex partners and having had sexually transmitted diseases, besides the poor hygiene, use of snuff, alcohol or contraceptives, and late detection, are main causes in the acquisition, manifestation and progression of cervical cancer. Objective: To determine the anticancer activity of 6-10 and 11-15 fractions of ethanolic extract of Sternocereusgriseus H in a model cell lines HeLa. The main objective of this work is to determine the cytotoxic activity of secondary metabolites obtained from various fractions of ethanol extract of Sternocereusgriseuss. the fruits in the Merced Market, which came from the State of Veracruz were purchased. The fruit was placed in a percolator and 6.5 liters of ethanol was added 96 °, the mixture was allowed to stand at room temperature for 5 days. Then it evaporated under reduced pressure to a crude extract, which she underwent preliminary chemical tests. Will extract was subjected to various chromatography techniques, using different stationary and mobile phases. Fractions had similar Rf gathered. To determine the cytotoxic activity of Vero cells culture and HeLa cells was performed by incubating for 12 hours, the time elapsed proceeded to add the extract fractions Sternocereusgriseuss H at different concentrations and incubated for 12 hours. At the end of this time, the cells were recovered and preceded to staining with annexin V-FITC and propyl iodide to determine the antitumor activity of fractions. Inextract Sternocereusgriseuss H were identified xanthones, flavones, aurones, coumarins and other phenolic compounds, triterpenes and reducing sugars. Column chromatography of fractions 1-5 and 11-15 two cytotoxic activities in the HeLa cell line were isolated.The two isolated fractions produced apoptotic activity and fraction 11 -15 showed higher activity necrosis and apoptosis.

Time:

Title: Targeting cytoskeletal aberrations to prevent breast cancer metastasis

Michele I. Vitolo
University of Maryland School of Medicine, USA

Biography

After attending Franklin and Marshall College, Dr. Vitolo began her career as a laboratory technician. After a few years, she returned to school to obtain her Ph.D. in Biochemistry from the University of Maryland Baltimore where she is currently an Assistant Professor. Dr. Vitolo has a long-standing interest in the molecular genetics of cancer. Her work focuses on the loss of the tumor suppressor PTEN and the progression of breast cancer. Over the years she has co-authored 29 publications and has acquired funding from numerous sources including the American Heart Association, Susan G. Komen Organization, American Cancer Society, and the National Cancer Institute.

Abstract

Patients diagnosed with triple negative breast cancer (TNBC) develop detectable metastatic disease within an average of only three years, and virtually all women with metastatic TNBC will die of their disease despite treatment. The short time period for developing metastases is due to presence of disseminated disease. Disseminating tumor cells circulate within the bloodstream during an intermediate step of the metastatic cascade. An increase in disseminating tumor cells correlates with disease progression and thus the number of circulating tumor cells are used for diagnostic purposes. However, very little is known about their biology. When in the bloodstream, these tumor cells are in a detached and free-floating state. Recently, we demonstrated that the regulation of the actin cytoskeleton differs in attached versus detached cells, leading to the conclusion that there are crucial targetable cytoskeletal signaling changes specific to detached, disseminating cells. In only detached cells, we determined that PTEN regulates the actin severing protein, cofilin, via a PI3K-independent mechanism. PTEN loss promotes cofilin activation leading to a weakened actin cortex. The weakening of the actin cortex increases cell deformability to enhance both tumor cell survival and cell reattachment. Our objective is to elucidate the mechanism by which PTEN regulates cofilin in detached cells to gain a greater understanding of how disseminating tumor cells control deformability. We hypothesize that PTEN loss weakens the actin cortex which enhances disseminated tumor cell deformability to promote metastatic efficiency. An improved understanding of the biochemical signals which modulate cytoskeletal alterations specifically in detached TNBC cells will provide new insight into the development of pharmacologic approaches for inhibiting metastasis by regulating cell deformability.

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Title: Dissecting molecular networks of leptin in breast cancer: Complexities and opportunities

Dipali Sharma
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, USA

Biography

Sharma attained her Ph.D. in Oncology followed by postdoctoral training at University of Maryland and Johns Hopkins University. Dr. Sharma is an Associate Professor of Oncology at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. Her lab focuses on investigating the molecular links between obesity and cancer, emphasizing aspects that have potential clinical significance. They are exploring new strategies to disrupt obesity-cancer connection using a variety of approaches. Their overall goal is to understand the molecular networks by which obesity affects carcinogenesis and discover novel agents to effectively disrupt obesity-cancer axis.

Abstract

Perturbations in the adipocytokines-profile, especially higher levels of leptin, are a major cause of breast tumor progression and metastasis. The focus of this talk is to discuss the impact of obesity on cancer with a special focus on breast cancer, discuss the underlying molecular mechanisms and discuss the potential therapeutic opportunities

Time:

Title: FOXO3a-driven epigenetic alternation of metabolism dictates the gemcitabine sensitivity of pancreatic cancer

Ching-Feng Chiu
National Institute of Cancer Research, National Health Research Institutes, Taiwan

Biography

Ching-Feng Chiu has completed his Ph.D from National Cheng Kung University of Taiwan and postdoctoral studies from Taipei Medical University and National Health Research Institutes. Now he serves as an Independent-Postdoctoral Fellowship of National Institute of Cancer Research in National Health Research Institutes, and hisstudies focus onthe roles of microRNAs and metabolism in tumor metastasisand drug resistance from basic research to clinical application. Over the past 5 years, he has published more than 12 original research papers, and he was awarded the9th National Innovation Award in 2012 and obtainedthe three-year research grant of Ministry of Science & Technologyof Taiwan in 2015.

Abstract

Gemcitabine has been a first-line therapeutic agent for pancreatic ductal adenocarcinoma (PDAC); however, the acquisition of resistance to gemcitabine remains a major challenge.Here, we investigated the metabolite profiles by liquid chromatography-mass spectrometry between gemcitabine–resistant PDAC and parental PDAC cells, and found that lactic acid amount and lactate dehydrogenase activity were increased in gemcitabine–resistant PDAC cells. We observed the elevated lactate dehydrogenase A (LDHA) expression significantly correlated with recurrent pancreatic cancer patients following gemcitabine treatment and with cancer stem cell (CSC) properties. By approachingthe comparative array-based microRNA (miRNA)expression and miRNA transcription analysis, we further identified that FOXO3a-induced miR-4259 directly targeted the 3’untranslated region ofLDHA and reduced LDHA expression, leading to decreased gemcitabine resistance and a reduction in the CSC phenotypes of pancreatic cancerin vitro and in vivo. Our findings suggest that LDHA might serve as a potential prognostic markerand therapeutic target for pancreatic cancer, particularly gemcitabine-resistant pancreatic cancer, and may provide evidence of an underlying epigenetic regulation of LDHA by FOXO3a/miR-4259, which appears to be involved in cancer stemness and the chemoresistance of pancreatic cancer.

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Title: The role of ovarian varicose veins and varicocele in cancer and venous thrombosis

Kennedy Goncalves Pacheco
Member of the Brazilian Society SBACV, Brazil

Biography

Abstract

Background Changes in the ovaries’ and the testicles’ phenotypes are associated to an increase in the risk of cancer and venous thrombosis. Varicocele and ovarian varicose veins can change the phenotype of the germinating glands. In this study, we made it our goal to evaluate the prevalence of ovarian varicose veins and varicocele in patients with cancer and venous thrombosis. Material and Method 54 patients with cancer and 98 patients in the control group who were diagnosed with venous thrombosis were included in this study. All of these patients were examined through ultrasound with vascular Doppler in order for us to investigate varicocele in men and ovarian varicose veins in women. Result Of a total of 14,800 patients, 152 with cancer and venous thrombosis were selected (1.02%). The group with cancer presented a significantly (p = 0.0029) higher proportion of varicose veins (96.3%) next to the germinating glands than the group with venous thrombosis (84.7%). The comparison between the groups with cancer and venous thrombosis was evaluated by the χ2test or the Fisher exact. The significance criteria adopted was the level of 5%. Conclusion The group with cancer presented a significantly higher proportion of varicose dilation than the group with venous thrombosis. Varicose veins next to the testicles and the ovaries are associated to oxidative stress, which can change the phenotype of germinating glands, provoking abnormalities in the hypothalamic-pituitary-gonadal axis, interfering in gene mutation in patients with cancer and venous thrombosis.

Sessions:
Cancer Drug Discover, Development and Delivery

Time:

Title: Targeting BCL6 for the treatment of DLBCL using the Site Identification by Ligand Competitive Saturation (SILCS) technology

Alexander D. MacKerell, Jr.
University of Maryland, USA

Biography

Alex MacKerell received an A.S. in Biology from Gloucester County College, a B.S. in Chemistry from the University of Hawaii and a Ph.D. in Biochemistry from Rutgers University. Subsequent training involved postdoctoral fellowships in the Department of Medical Biophysics, KarolinskaIntitutet, Stockholm, Sweden in experimental and theoretical biophysics and in the Department of Chemistry, Harvard University in theoretical chemistry. MacKerell is currently the Grollman-Glick Professor of Pharmaceutical Sciences in the School of Pharmacy, University of Maryland, Baltimore and the Director of the University of Maryland Computer-Aided Drug Design Center. MacKerell is also Co-founder and Chief Scientific Officer of SilcsBio LLC. Research interests include the development of theoretical chemistry methods, with emphasis on empirical force fields, including the CHARMM additive and Drude polarizable force fields, structure-function studies of proteins, carbohydrates and nucleic acids, and drug design and development.

Abstract

The BCL6 oncogene is constitutively activated by chromosomal translocations and amplification in ABC-DLBCLs, a class of DLBCLs that respond poorly to current therapies. BCL6 mediates its effects by recruiting corepressors to an extended groove motif thereby repressing expression of selected proteins, including those in checkpoint pathways and IRF4 and PRDM1, thereby blocking plasma cell differentiation. Accordingly, we have undertaken a drug design campaign to develop inhibitors of BCL6-corepressor interactions. Towards this goal we applied the Site Identification by Ligand Competitive Saturation (SILCS) methodology in conjunction with synthetic chemistry, structural biology and biological evaluation. SILCS involves the calculation of functional group affinity maps of proteins; these “FragMaps” take into account protein flexibility, protein and functional group desolvationpenalties as well as protein-functional group interactions. FragMaps may be used to qualitatively direct ligand design as well as quantitative predict relative binding affinities of 1000s of compounds on a daily basis, at an accuracy comparable to free energy perturbation, thereby allowing SILCS to lead the drug design process. Based on the SILCS approach, the role of functional groups to affinity was determined for the lead compound, 79-6,targeting BCL6, acting as the basis for the design and in silico evaluation of lead compound analogs. Subsequent synthesis and experimental evaluation of the predicted compounds showed them to bind to BCL6 in the predicted binding orientation. Notably, the new compound, termed FX1, has an affinity for BCL6 higher than that of the corepressors indicating its potential as a drug candidate. FX1 disrupts BCL6 repression complex formation, reactivates BCL6 target genes, and mimics the phenotype of mice engineered to express BCL6 with lateral groove mutations. This compound eradicated established DLBCLxenografts at low doses. Most strikingly, FX1 suppressed ABC-DLBCL cells as well as primary human ABC-DLBCL specimens ex vivo.

Time:

Title: KDM4/JMJD2 histone demethylase inhibitors block prostate tumor growth by suppressing the expression of AR and BMYB-regulated genes

Zhi-Ping Liu
UT Southwestern Medical Center, USA

Biography

Dr. Zhi-Ping Liu obtained her PhD in Biophysics and post-doctoral training in Molecular Biology at UT Southwestern Medical Center. She is now an associate professor in the department of internal medicine, UT Southwestern. Her research focuses on the transcriptional regulation of genes involved in cancer and cardiovascular diseases.

Abstract

Histone lysine demethylase KDM4/JMJD2s are overexpressed in many human tumors including prostate cancer (PCa). KDM4s are co-activators of androgen receptor (AR) and are thus potential therapeutic targets. Yet to date few KDM4 inhibitors that have anti-prostate tumor activity in vivo have been developed. Here, we report the anti-tumor growth effect and molecular mechanisms of three novel KDM4 inhibitors (A1, I9, and B3). These inhibitors repressed the transcription of both AR and BMYB-regulated genes. Compound B3 is highly selective for a variety of cancer cell lines including PC3 cells that lack AR. B3 inhibited the in vivo growth of tumors derived from PC3 cells and ex vivo human PCa explants. We identified a novel mechanism by which KDM4B activates the transcription of Polo-like kinase 1 (PLK1). B3 blocked the binding of KDM4B to the PLK1 promoter. Our studies suggest a potential mechanism-based therapeutic strategy for PCa and tumors with elevated KDM4B/PLK1 expression.

Time:

Title: Seeking novel anticancer strategies around the druggable clock

Grimaldi Benedetto
Istituto Italiano di Tecnologia (IIT), Italy

Biography

Dr. Benedetto Grimaldi obtained in 2001 the degree in Biological Science with a summa cum laude from the University of Rome “La Sapienza”. After obtained a PhD in Genetics and Molecular Biology at University of Rome, specializing in the study of epigenetics and signal transduction, Dr. Grimaldi transitioned into a postdoctoral fellowship under the mentorship of Prof. Sassone-Corsi (University of California, Irvine, USA), a leader in the field of circadian clock, metabolism and epigenetics. Since 2015, Dr. Grimaldi works as a Senior Researcher at the IstitutoItaliano di Tecnologia (Italy), focusing on the study of the links between clock factors and human pathologies, and on the identification and evaluation of novel molecules with “clock modulator” activity for therapeutic applications.

Abstract

Disruption of the circadian clock has been associated with a variety of human pathologies, including metabolic dysfunctions and cancer. Nevertheless, whether pharmacological targeting of circadian regulators is a viable approach to cancer therapy remained to be determined. We recently reported that the circadian regulator REV-ERBβ is overexpressed in many tumor cells and it plays an unexpected role in sustaining cancer cell survival when the autophagy flux is compromised. Our studies also identified the first compound with a dual inhibitory activity toward autophagy and REV-ERBβ, which showed a more potent anticancer activity than the clinically relevant autophagy inhibitor, chloroquine (CQ), against different human tumor tissue cells. Further structure-activity relationship (SAR) analysis on the hit compound identified a class of molecules with a higher inhibitory potency toward REV-ERBβ, resulting in higher cancer-specific cytotoxicity. Notably, in a number of CQ-resistant cancer cell lines, our dual REV-ERB/autophagy inhibitors inhibited growth at low micro-molar concentration, suggesting their use as novel anticancer agents for the treatment of chloroquine-resistant tumors. In addition, we obtained preliminary data indicating a REV-ERBβ-mediated regulation of cancer metabolism, which it has recently become one of the most exciting and promising areas for the development of antitumor drugs. As a consequence, REV-ERBβ inhibition may be suitable for combinatorial therapy with a number of metabolic-related anticancer agents. In addition to provide a scaffold for the development of novel anticancer agents, these dual inhibitors can be used as valuable pharmacological tool for elucidate novel crosstalk between circadian rhythm, cancer metabolism and autophagy.

Time:

Title: Regulation of HIF1expression by a natural compound; a new hnRNP involvement

Bo Yeon Kim
Korea Research Institute of Bioscience & Biotechnology, Korea

Biography

Dr. Bo Yeon Kim got Ph.D degree at Seoul National University in 1996. After the research fellow experience at Georgetown University, 2000-2003, he continued his work at Korea Research Institute of Bioscience & Biotechnology (KRIBB) for about 26 yrs so far. Major research focuses on identification of new cancer signaling pathways and development of a new anticancer drug with low side effect. In recent 5 years, He has made more than 65 publications, including Nature Cell Biology (2015), Autophagy (2016, 2013), Proc Natl Acad Sci, USA (2013), J Am Chem Soc (2011), J Biol Chem (2013, 2012), and under revision papers (Nature Communicaitons, EMBO Reports, Autophagy) as a corresponding author.

Abstract

Hypoxia induces HIF1expression, leading to the malignant cell transformation. In screening of inhibitors against HIF1expression using a reporter gene assay system, a moracin derivative, MOA, was found to strongly reduce the level of HIF1in HeLa cellsboth in hypoxia-mimetic CoCl2treatment and under hypoxic conditions. Identification of binding proteins using agarose-bead conjugated MOA(AC-685) combined with subsequent MS data revealed several proteins affected by MOA. AC-685 co-localized with a nuclear hnRNPX protein in CoCl2 treated HeLa cells. Amongst several cytoplasmic or nuclear proteins, hnRNPX was only found to be responsible for CoCl2-induced HIF1expression as supported by siRNA depletion of the protein. Cancer growth was also found to be reduced in a genograft animal model. This study suggests that regulation of HIF1expression by MOAunder the control of hnRNP would be a novel approach to cancer treatment in hypoxic environment.

Time:

Title: A new druggable site to rescue p53 folding and activity

John Karanicolas
Fox Chase Cancer Center, USA

Biography

John Karanicolas is currently an Associate Professor at the Fox Chase Cancer Center, in the Molecular Therapeutics Program. He was granted a PhD from Charlie Brooks' lab at The Scripps Research Institute in 2003, for his work using molecular dynamics simulations to study protein folding. He then moved to a postdoc in David Baker's lab at the University of Washington, where he studied protein design and added a wetlab component to his research. He started his lab at the University of Kansas in 2008, focusing on developing structure-based approaches for modulating protein function using small-molecules. He moved his lab to Fox Chase in 2016, where his research follows two parallel themes: the first is re-engineering proteins so that a small-molecule can be used to “turn on” function, and the second is identifying small-molecules that naturally complement and occlude a protein interaction sites to “turn off” function.

Abstract

The tumor suppressor protein p53 is mutated or deleted in more than half of human cancers. The most frequently occurring of these loss-of-function mutations are localized to the p53 “core domain,” but do not involve surface residues directly responsible for function. Rather, these point mutants reduce the thermodynamic stability of this marginally stable protein, such that cellular activity is diminished because an insufficient amount of p53 is correctly folded. We sought to identify compounds that bind and stabilize correctly folded p53, expecting that stabilization through this mechanism will restore activity to this most frequently occurring class of p53 point mutants, and further will restore activity to these destabilized mutants. Using new computational tools developed in my lab, we have discovered a new druggable site on the surface of the p53 core domain, and identified compounds designed to interact with this surface. Through biochemical assays we find that these compounds are effective at stabilizing multiple different p53 mutants. We further find that these compounds can restore transcriptional activity in cell lines harboring destabilized mutants of p53, without affecting cells that have wild-type p53. Thus, this new druggable site may provide a starting point for developing a new class of therapeutics that selectively re-activate p53 – regardless of precisely which mutation is responsible for the underlying loss of protein function.We also expect that refinement of our novel screening platform will additionally enhance its utility for identifying re activators of other select proteins that are frequently deactivated in human cancers by destabilizing mutations.

Time:

Title: MRI-based guidance for predictable and precise intra-arterial delivery of therapeutic agents to the central nervous system

Miroslaw Janowski
Johns Hopkins University School of Medicine, USA

Biography

Dr Janowski completed residency in neurosurgery at the Medical University of Warsaw, Poland and then moved to Department of Radiology at the Johns Hopkins University, USA where he holds a position of associate professor. His research is focused on the development of the precise methods to deliver high doses of therapeutic agents including drugs and stem cells to the desired areas of the brain.He has published over 40 papers in peer reviewed journals, edited a book on experimental neurosurgery, served as a program chair for workshop, chaired multiple sessions at international conferences and gave over 15 invited talks worldwide. His research is funded by NIH, DoD and Maryland Stem Cell Research Fund.

Abstract

Neurological disorders constitute one of the biggest medical challenges. Although there has been rapid progress in the treatment of peripheral malignancies over the last 20 years, the prognosis for brain tumors is imperturbably grim. However, many drugs, including melphalan, are highly effective in vitro. Moreover, intra-arterial delivery of high-dose melphalan radically changed the treatment of retinoblastoma, with a frequent cure rate, without the need for eye removal. However, melphalan, as well as many other antineoplastic agents, cannot effectively cross the blood-brain barrier, thus limiting their efficacy for the treatment of brain tumors. The opening of the blood brain barrier (BBB) to facilitate tumor penetration by drugs has been attempted for many years. Intra-arterial administration of hyperosmotic agents (IAHA) has been shown safe, but high variability of results was discouraging and the method has been almost abandoned. We have found that MRI contrast agents are sufficiently sensitive to report on the brain territory supplied by a catheter thus MRI is critically needed to guide the intra-arterial delivery of therapeutic agents to the brain. Superparamagnetic iron oxide nanoparticles (SPIO) are very attractive as contrast agents due to their very strong signal, which allows for a very short MRI acquisition time, e.g., two to three seconds, using a GE-EPI pulse sequence. This actually enables real-time monitoring of the territory supplied by the catheter. In addition, the SPIO clears rapidly after infusion discontinuation, which, in turn, allows for precise adjustments of the territory supplied by the catheter through manipulation of the speed of infusion and the catheter tip position. Moreover, we have shown that the delineation of the brain territory supplied by the catheter also allows for precise prediction of the subsequent BBB opening area, which, in turn, overcomes the previously reported problems with the variability of the BBB opening territory after IAHA. This then, allows for a new era of predictable and precise intra-arterial drug delivery to the brain (Janowski et al. 2015). Thus, in our opinion, the intra-arterial delivery of therapeutic agents through a predictable and precise blood brain barrier opening should always be attempted before the agent is deemed ineffective. Our method can also be potentially useful for other neurological disorders, such as neuroinflammatory and neurodegenerative conditions. 1. Janowski M, Walczak P and Pearl MS (2015). Predicting and optimizing the territory of blood-brain barrier opening by superselective intra-arterial cerebral infusion under dynamic susceptibility contrast MRI guidance. J Cereb Blood Flow Metab.2016 Mar;36(3):569-75

Time:

Title: Role of apoptosis regulators of the Bcl-2 family in the control of cell motility during development and tumor progression

Germain Gillet
University of Lyon, France

Biography

Dr. Germain GILLET is a Professor in the Université Claude Bernard Lyon 1 (UCBL), France and Chair, Scientific Council UCBL ; Group leader at CRCL. His current research is focused on The molecular mechanisms governing tumor progression, including metastasis development, are still poorly understood. We showed that some members of the Bcl-2 family are able to control cell migration in a Ca2+-dependent manner via their direct interactions with Ca2+ channels, independently of their involvement in apoptosis. Using genetically engineered mouse and zebrafish models, we are analyzing the molecular mechanisms by which members of the Bcl-2 family influence cell survival and cell migration. We intend to (i) identify the signaling networks that lead to the modulation of Ca2+ homeostasis and cell movements by Bcl-2 family proteins (ii) identify the factors involved in apoptosis progression and cell migration (iii) review the roles played by these factors, depending on the pathophysiological context. It is anticipated that this work will lead to the identification of novel prognosis markers and might deliver potential molecular targets for the control of tumor-growth and formation of metastases.

Abstract

Local invasion can be considered as an initial and essential step in the malignancy of carcinomas, leading to the generation of distant metastasis. Metastasis remains the major cause of cancer-related mortality and currently, there is a lack of therapies that can efficiently prevent this process.The molecular mechanisms governing tumor progression, including metastasis development, are still poorly understood. During this process, cells acquire apoptosis resistance which is often correlated with alteration of Bcl-2 family proteins status. Bcl-2 family members are the main regulators of apoptosis. Upregulation of the anti-apoptotic members in wide range of cancers including breast cancer is often correlated with chemotherapy resistance and poor prognosis. Thus targeting the activity of Bcl-2 family proteins represents promising strategies for the elaboration of cancer therapeutic. Bcl-2 proteins have been studied intensively for the past two decades owing to their importance in the regulation of apoptosis, tumorigenesis and cellular responses to anti-cancer therapy. However, increasing data suggest additional roles, including regulation of the cell cycle, metabolism and cytoskeletal dynamics. Using zebrafish as a vertebrate model we demonstrated that two Bcl-2 homologs, Nrz and Bcl-wav, orchestrate morphogenic movements by controlling the intracellular Ca2+ trafficking during early development. Nrz silencing causes development arrest followed by detachment of the entire blastomeres from the yolk sac. Time-lapse and confocal microscopy experiments demonstrated that this phenotype is due to the premature formation of actin-myosin complexes, giving rise to a contractile structure that squeezes the embryo margin and prevents epiboly progression. At the ER membranes, Nrz interacts with the IP3 binding domain of the IP3R1 Ca2+ channel. This interaction regulates the time course of Ca2+ transients in the yolk sac that consecutively controls the formation of actin-myosin cables via the CaMKII-MLCK pathway. Put into a broader context our results established for the first time that members of the Bcl-2 family are able to control cell migration in a calcium dependent manner via their direct interaction with intracellular Ca2+ channels and thus independently of their involvement in the regulation of cell death.Togetherourresultsmayalsocontribute to a betterunderstanding of the molecularmechanismsunderlyingmetastasis formation.

Time:

Title: Effects of anticancer drugs on Chromosome Instability (CIN) and new clinical implications for tumor-suppressing therapies

Natalay Kouprina
National Cancer Institute, NIH, USA

Biography

Natalay Kouprina received her M.Sc. in physical chemistry from the St. Petersburg State University, Russia, and her Ph.D. and Dr.Sc. in cell biology from the Institute of Cytology, Russian Academy of Sciences. While in Russia, she worked on the identification of genes that control the replication and segregation of chromosomes in budding yeast. In 1991 she moved to the United States and focused her interests on human genome. Her current interest is to combine a transformation-associated recombination (TAR) cloning technology for selective isolation of a large segments from complex genomes with the human artificial chromosome (HAC) –based vectors to develop a novel system for delivery and expression of full-length mammalian genes for functional genomics that has a great potential for gene therapy. At present she is a staff scientist at the National Cancer Institute, NIH, USA. She has 101 publications in many leading international journals and 7 US patents. She is an editorial board member of several international journals. She was an Invited Guest Editor of special issues of few journals. Natalia Kouprina was a co-organizer of several international conferences.

Abstract

Whole-chromosomal instability (CIN), manifested as unequal chromosome distribution during cell division, is a distinguishing feature of most cancer types. CIN is generally considered to drive tumorigenesis, but a threshold level exists whereby further increases in CIN frequency in fact hinder tumor growth. While this attribute is appealing for therapeutic exploitation, drugs that increase CIN beyond this therapeutic threshold are currently limited. In our previous work, we developed a quantitative assay for measuring CIN based on the use of a non-essential human artificial chromosome (HAC) carrying a constitutively expressed EGFP transgene. Here, we used this assay to rank 62 different anticancer drugs with respect to their effects on chromosome transmission fidelity. Drugs with various mechanisms of action such as antimicrotubule activity, histone deacetylase (HDAC) inhibition, mitotic checkpoint inhibition, and targeting of DNA replication and damage responses were included in the analysis. Ranking of the drugs based on their ability to induce HAC loss revealed that paclitaxel, gemcitabine, dactylolide, LMP400, talazoparib, olaparib, peloruside A, GW843682, VX-680, and cisplatin were the top ten drugs demonstrating HAC loss at a high frequency. Therefore, identification of currently used compounds that greatly increase chromosome mis-segregation rates should expedite the development of new therapeutic strategies to target and leverage the CIN phenotype in cancer cells.

Sessions:
Cancer Genetics and Biomarkers & Clinical Research

Time:

Title: Perioperative use of NSAID might prevent early relapses in breast and other cancers: An upstream approach

Michael Retsky
Harvard TH Chan School of Public Health, USA

Biography

Michael Retsky (PhD in Physics from University of Chicago) made a career change to cancer research thirty years ago. He is on staff at Harvard TH Chan School of Public Health and faculty at University College London. He was on Judah Folkman’s staff at Harvard Medical School for 12 years. Retsky is Editor of a Nature/Springer book on breast cancer to be published in 2016 and Editor-in-Chief of the Journal of Bioequivalence and Bioavailability. He is a founder and on the Board of Directors of the Colon Cancer Alliance and has published more than 60 papers in physics and cancer.

Abstract

A bimodal pattern of hazard of relapse among early stage breast cancer patients has been identified in multiple databases from US, Europe and Asia. We are studying these data to determine if this can lead to new ideas on how to prevent relapse in breast cancer. Using computer simulation and access to a very high quality database from Milan for patients treated with mastectomy only, we proposed that relapses within 3 years of surgery are stimulated somehow by the surgical procedure. Most relapses in breast cancer are in this early category. Retrospective data from a Brussels anesthesiology group suggests a plausible mechanism. Use of ketorolac, a common NSAID analgesic used in surgery was associated with far superior disease-free survival in the first 5 years after surgery. The expected prominent early relapse events in months 9-18 are reduced 5-fold. Transient systemic inflammation accompanying surgery (identified by IL-6 in serum) could facilitate angiogenesis of dormant micrometastases, proliferation of dormant single cells, and seeding of circulating cancer stem cells (perhaps in part released from bone marrow) resulting in early relapse and could have been effectively blocked by the perioperative anti-inflammatory agent. If this observation holds up to further scrutiny, it could mean that the simple use of this safe, inexpensive and effective anti-inflammatory agent at surgery might eliminate early relapses. We suggest this would be most effective for triple negative breast cancer and be especially valuable in low and middle income countries. Similar bimodal patterns have been identified in other cancers suggesting a general effect.

Time:

Title: Evolution by Tumor Neofunctionalization and Phenomenon of Tumor Specifically Expressed, Evolutionarily Novel (TSEEN) genes

A.P.Kozlov
Biomedical Center and Peter the Great St.Petersburg Polytechnic University, Russia

Biography

Andrei P. Kozlov, Ph.D., Dr.Sci., Professor of Molecular Biology, was born in Leningrad in 1950. In 1972 he graduated with honors from St. Petersburg State University (Department of Biochemistry). During the period 1972-1975, he completed postgraduate studies at the N.N. Petrov Research Institute of Oncology and successfully defended his Ph.D. thesis devoted to the studies of low molecular weight nuclear RNAs in normal and tumor tissues. In 1978-1979 Dr. Kozlov served in a tenured Research Training Fellowship awarded by the International Agency for Research on Cancer at the laboratory of Robert Gallo at the National Cancer Institute.

Abstract

Earlier I formulated the hypothesis of the possible evolutionary role of tumors. This hypothesis suggests that tumors supply evolving multicellular organisms with extra cell masses for the expression of newly evolving genes. After expression of novel genes in tumor cells, tumors differentiate in new directions and give rise to new cell types, tissues and organs. In the presentation, the bulk of data supporting the positive evolutionary role of tumors will be reviewed, obtained both in the lab of the author and from the literature sources. The following issues will be addressed: the widespread occurrence of tumors in multicellular organisms; features of tumors that could be used in evolution; the relationship of tumors to evo-devo; examples of recapitulation of some tumor features in recently evolved organs; the types of tumors that might play the role in evolution; examples of tumors that have played the role in evolution. The discussion of experimental confirmation of nontrivial predictions of the hypothesis will include the analysis of evolutionary novelty of tumor-specifically expressed EST sequences; ELFNI – AS1, a human gene with possible microRNA function expressed predominantly in tumors and originated in primates; PBOV1, a human gene of the recent de novo origin with predicted highly tumor-specific expression profile; the evolutionary novelty of human cancer/testis antigen genes; etc. The conclusion is made that expression of protogenes, evolutionarily young and/or novel genes in tumors might be a new biological phenomenon, a phenomenon of TSEEN (Tumor Specifically Expressed, Evolutionarily New) genes, predicted by the hypothesis of evolution by tumor neofunctionalization.

Time:

Title: Epigenetic rewiring of breast cancer by targeting a metabolic switch

Jung S. Byun
Center for Cancer Research, National Cancer Institute, USA

Biography

Dr. Jung S. Byun received her Ph.D. in chemistry and biochemistry from the University of Maryland, College Park. She pursued postdoctoral studies with Dr. Kevin Gardner at NCI, National Institutes of Health. During her postdoctoral residency, Dr. Byun carried out studies to define how histone acetyltransferase, p300, and the elongation factor, ELL, work in concert to control eukaryotic transcription by demonstrating the role of dynamic bookmarking by p300 RNA polymerase II complexes in transcriptional memory. She also discovered a new role for ELL (Eleven-nineteen Lysine-rich Leukemia protein), that it is required for early elongation and facilitating pol II pause site entry. Dr. Byun is currently a staff scientist with Dr. Kevin Gardner’s laboratory. The lab's research interests focus on characterizing other potential transcription regulatory targets important in mammalian cancer cell biology that define a molecular link between metabolic imbalance and breast cancer and how this can modify risk and outcome to decrease health disparities in cancer.

Abstract

Dr. Jung S. Byun received her Ph.D. in chemistry and biochemistry from the University of Maryland, College Park. She pursued postdoctoral studies with Dr. Kevin Gardner at NCI, National Institutes of Health. During her postdoctoral residency, Dr. Byun carried out studies to define how histone acetyltransferase, p300, and the elongation factor, ELL, work in concert to control eukaryotic transcription by demonstrating the role of dynamic bookmarking by p300 RNA polymerase II complexes in transcriptional memory. She also discovered a new role for ELL (Eleven-nineteen Lysine-rich Leukemia protein), that it is required for early elongation and facilitating pol II pause site entry. Dr. Byun is currently a staff scientist with Dr. Kevin Gardner’s laboratory. The lab's research interests focus on characterizing other potential transcription regulatory targets important in mammalian cancer cell biology that define a molecular link between metabolic imbalance and breast cancer and how this can modify risk and outcome to decrease health disparities in cancer.

Time:

Title: ElastofibromaDorsi (ED): Oncological significance and impact on management

Mohamed Elshikh
The University of Texas MD Anderson Cancer Center, USA

Biography

Mohamed Elshikh is a postdoctoral fellow in Diagnostic Radiology Department at The University of Texas MD Anderson Cancer Center. He is currently investigating role of CT and PET-CT in assessing treatment response in hematological malignancies patients.

Abstract

Objective: To investigate the association of ED with other malignancies. Methods: A case-control trial was conducted to investigate prevalence of ED with other malignancies. Cases represented patients who are diagnosed with elastofibeoma (52 patients). Control cases were randomly selected from patients who did CT scan in our institution (150 patients). Results: 10 ED patients and 15 control patients did not have any neoplastic process. 19 malignant diseases affecting 8 systems were found in ED patients. Hematological malignancies; namely diffuse large B-cell lymphoma (DLBCL) were the most common malignant disease in elastofibroma patients followed by genitourinary malignancies. 56 neoplastic diseases were found in the control group affecting 11 systems; 3 were benign and 53 were malignant. Lung and colon cancers were the most common malignancies in the control group followed by prostate cancer. ED patients had a significantly higher probability of having hematological malignancies than the control group (P-value = 0.002). ED patients were at a higher risk of having DLBCL than the control group (P-value = 0.029 and 0.001 when using non-cancer and other cancers as a reference respectively). When genitourinary cancers were used as a reference group for comparison of ED patients with the control group, ED patients were not at a high of having genitourinary cancers (P-value = 0.39 and 0.27, on comparison with non-cancer and other system cancers respectively). Conclusion: ED patients at a higher risk of developing hematological malignances especially DLBCL and clinical surveillance is needed.

Time:

Title: Potential clinical implications of breast tumor kinase in ER-positive breast cancers

Kiven E. Lukong
University of Saskatchewan, Canada

Biography

Dr. Kiven Erique Lukong received his Ph.D. degree in biochemistry from the University of Montreal in Canada and pursued his post-doctoral training first at Harvard Medical School, U.S.A. and later at McGill University (Canada). He is currently an Associate Professor in the Department of Biochemistry at the University of Saskatchewan (U of S, Canada) since 2009 and a member of the Cancer Research Cluster at the U of S. Since beginning his independent academic career at the U of S, Dr. Lukonghas obtained career awards from the Saskatchewan Health Research Foundation (SHRF, Top New investigator 2010) and from the Canadian Institutes of Health Research (CIHR, New investigator salary award).Dr. Lukong’s research broadly involves elucidating the signaling mechanisms that control growth of normal and cancer cells. His lab is investigating the cellular and physiological roles, and the mechanisms of action and modes of regulation of the breast tumor kinase (BRK) family of non-receptor tyrosine kinases in breast cancer and glioblastoma. The Lukong lab is also characterizing the diagnostic, prognostic and therapeutic potential of the BRK family proteins in breast cancer. Dr. Lukong holds or has held funding from SHRF, CIHR and the Canadian Breast Cancer Foundation.

Abstract

Dr. Kiven Erique Lukong received his Ph.D. degree in biochemistry from the University of Montreal in Canada and pursued his post-doctoral training first at Harvard Medical School, U.S.A. and later at McGill University (Canada). He is currently an Associate Professor in the Department of Biochemistry at the University of Saskatchewan (U of S, Canada) since 2009 and a member of the Cancer Research Cluster at the U of S. Since beginning his independent academic career at the U of S, Dr. Lukonghas obtained career awards from the Saskatchewan Health Research Foundation (SHRF, Top New investigator 2010) and from the Canadian Institutes of Health Research (CIHR, New investigator salary award).Dr. Lukong’s research broadly involves elucidating the signaling mechanisms that control growth of normal and cancer cells. His lab is investigating the cellular and physiological roles, and the mechanisms of action and modes of regulation of the breast tumor kinase (BRK) family of non-receptor tyrosine kinases in breast cancer and glioblastoma. The Lukong lab is also characterizing the diagnostic, prognostic and therapeutic potential of the BRK family proteins in breast cancer. Dr. Lukong holds or has held funding from SHRF, CIHR and the Canadian Breast Cancer Foundation.

Time:

Title: Developing precision therapies for glioblastoma by targeting glioblastoma stem cells

Zhi Sheng
Virginia Tech Carilion Research Institute, USA

Biography

Dr. Sheng obtained his PhD at the State University of New York Downstate Medical Center in 2005. He conducted his postdoc research focusing on delineating cancer cell survival pathways in leukemia and glioblastoma in Dr. Michael Green’s laboratory at the University of Massachusetts Medical School. He is currently an assistant professor at the Virginia Tech Carilion Research Institute. His research team has recently identified several new survival pathways in glioblastoma and they are investigating how to translate their findings into precision therapies for glioblastoma.

Abstract

Dr. Sheng obtained his PhD at the State University of New York Downstate Medical Center in 2005. He conducted his postdoc research focusing on delineating cancer cell survival pathways in leukemia and glioblastoma in Dr. Michael Green’s laboratory at the University of Massachusetts Medical School. He is currently an assistant professor at the Virginia Tech Carilion Research Institute. His research team has recently identified several new survival pathways in glioblastoma and they are investigating how to translate their findings into precision therapies for glioblastoma.

Time:

Title: Cellular mechanotypical property as a novel biomarker for cancer

Jianyu Rao
University of California at Los Angeles, USA

Biography

Dr. Rao is a tenured full professor of pathology and epidemiology at University of California at Los Angeles (UCLA). He is the chief of Cytopathology, the ex-director of gynecological pathology, the director of international telepathology, and the medical director of cytotechnology school. He is a fellow of College of American Pathologist (FCAP), Fellow of Academy of Translational Medicine (FacdTM), Member of Jonsson Comprehensive Cancer Center, a Member of California Nanosystem Institute, aGuangji Scholar and visiting professor at Zhejiang University, and elected-recipient of Thousand-Talent Program, China. He has over 150 peer-reviewed publicationsand been a speaker for over 150 meetings and occasions locally, nationally and internationally for variety topics including cancer biomarkers,screen and prevention, cytology, pathology, and nanotechnology. His notable accomplishments include established the first-ever international Telepathology program, investigated mechanisms of cytoskeletal actin remodeling in cancer development and progression, and studied cellular nano-mechanical profiling as a biomarker for cancer.

Abstract

The hallmark of cancer is the invasive and metastatic nature of the disease. Cancer cell invasion and metastasis are partly regulated by altered cytoskeletal structures that result from the complex interplay of activation/inactivation of multiple signaling pathways regulating these cellular events, which can occur at either the genetic or epigenetic level. Thus, attempts to accurately assess these physiologically relevant mechanical properties of cancer cells using single, or even multiple marker profiles at the DNA, RNA, or protein level, may not be effective. Recently we showed that cancer cell mechanical properties, or mechanotypic biomarkers, including cell elasticity and deformability can be directly and accurately measured by state of the art, label-free technologies at the single cell level. These mechanical properties of cells can be a marker for cancer cell behavior including invasion, metastasis, and drug response. We developed an approach that uses mechanotypic profiling to complement morphological and molecular analyses, a process called “Nanocytology” which collectively enable robust and high throughput measurements and can potentially be implemented even in resources poor areas. The nanocytology approach combined with targeted delivery of nanoparticles with molecular-tailored anti-cancer agents may provide a more effective alternative for cancer detection and management.

Time:

Title: Normal and cancer stem cells

Chaker Adra
Chief Scientific Officer &Chief Technology Officer, ACIAM-BFSRI, USA

Biography

Chaker Adra is investigating health, disease, and pioneering the field of organ engineering and regenerative medicine. He is discovering the Laws of Physics & Chemistry as manifested in The Language of Genomes and Living Organisms. He contributed to the emergence of the field of stem cell biology & tissue engineering. He cloned, characterized the family of phosphoglycerate kinase (PGK) genes and pseudogenes. He identified the PGK-1 promoter which has proven to be a powerful and widely used promoter. He designed and constructed The PGK1-Neo Shuttle which is being used around the world for gene therapy, to engineer, from embryonic stem cells, transgenic and knockout animals to understand the causes and mechanisms of all human diseases and find cures. He cloned the pgk-2 gene, showing for the first time that gene duplication, by retroposition more than 100 million years ago, have been used as a mechanism for evolutionary diversification and that mammalian genomes are fluid creating new species. He identified chromosomal regions containing asthma and atopy susceptibility genes. He described functional polymorphisms in Interleukin-4, IL-13 and their receptors, thus making these molecules, with STAT 6, targets for therapeutic treatment of allergic patients and preventive strategies. He discovered several cancer and stem cell specific biomarkers. In a series of groundbreaking experiments, he discovered several universal gene families and biochemical and/or physiological pathways operating in bacteria, yeast, plants, animals and humans (PGK, D4GDI/RhoGDI2/ARHGDIB, RhoGDI3/ARHGDIG, RTEF-1, HTm4/CD20L/MS4A Gene Family, LAPTM5, SMARCAD1 Helicase Gene Family, and SMARCAD1, The Fingerprints Gene). Dr. Chaker Adra is a philanthropist and the inventor of 19 USA and International Patents.

Abstract

Cancers initiate and develop from rare population of stem-like cells termed as cancer stem cells (CSC). Our goal is to identify and define the single normal and cancer stem cell of every human tissue in order to succeed in cancer and stem cell therapy, organ engineering, reconstructive and cosmetic surgery.The exact phenotype of CSC and their counterparts in normal mammary gland is not well characterized. We show that CSC are predominantly CD49f + proposing the use of CD44high/CD24low in combination with Ep-CAM/CD49f cell surface markers to further enrich for CSC.Our profiling demonstrates that both normal and breast cancer cells with the CD44high/CD24low phenotype have the highest stem/progenitor cell ability when used in combination with Ep-CAM/CD49f reference markers. Our protocols help understand breast cancer, cancers heterogeneity, drug resistance, towards eradicating the roots of all cancers.

Time:

Title: CpG methylation in the TERT promoter

Josh L. Stern
University of Colorado Boulder, USA

Biography

Dr. Stern was awarded his Ph.D from the University of Sydney in Australia before commencing his postdoctoral training at the The University of Colorado in Boulder in the lab of Dr. Thomas Cech. Dr. Stern is focused on understanding the mechanisms that govern telomerase and telomere biology, in both normal and disease contexts, to identify therapeutic targets for the treatment of cancer,as well as other telomere-based diseases.

Abstract

Epigenetic modifications in gene regulatory regions significantly contribute to the chromatin landscape that favors or disfavors transcriptional activation. One of the most abundant and least understood epigenetic modifications in eukaryotic DNA is methylation of cytosines at C-G dinucleotides (CpG). High levels of methylation in CpG rich gene promoters is typical of silenced genes; in contrast CpG methylation in gene bodies is canonically associated with expressed genes. Telomerase reverse transcriptase (TERT) is an important oncogene on which 85-90% of all cancers rely for their indefinite replication. Methylation of the CpG island (cg11625005) in the proximal TERT promoter in cancer differs markedly from stem cells and differentiated cells. While normal cells exhibit little or no methylation at this locus, existing studies report that nearly all cancers exhibit significant levels of methylation at this CpG island. In contrast to expectations from other genes, numerous studies report that global demethylating agents such as azacytidine are detrimental to TERT mRNA expression in most cancers. We are working on understanding this confounding observation using a subset of cancer cells that express TERTmonoallelically. In these cancers, in a single cell, one allele is active, while other TERT alleles are not expressed. Our data indicate that cancers with both active and silent alleles in the same cell display differential methylation patterns at cg11625005 on the different alleles. Targeted epigenome editing of these loci result in phenotypes that differ from previous reports that utilized global demethylating treatments. We conclude that the consequences of CpG methylation in the TERT promoter may be more complex than existing studies suggest.

Time:

Title: A novel biomarker for NSCLC

Shiyang Pan
Nanjing Medical University, China

Biography

Professor Shiyang Pan has studied lung cancer over 20 years, during which time he has found novel biomarkers for NSCLC and authored more than 100 peer-reviewed reports. He has served on the editorial board for the Chinese Journal of Laboratory Medicine. Dr. Pan is the director of the Laboratory Medicine Department of Nanjing Medical University and the National Key Clinical Department of Laboratory Medicine. He is the Chairman of the Jiangsu Society of Laboratory Medicine, and a member of the Standing Committee of Chinese Society of Laboratory Medicine, and he has served on review committees for the NSFC and Health Administration of China.

Abstract

Monoclonal antibody (McAb) is the key tool for cancer immunodiagnosis and immunotherapy. In this study, a cell clone which kept secreting high-titer IgG1-type McAb named NJ001 against human non-small cell lung cancer (NSCLC) cells was obtained. The antigen named SP70 of NSCLC specifically identified by NJ001 was proved to be a protein with the relative molecular mass (Mr) of 70kDa. The results of immunohistochemical staining indicated that NJ001 could positively react to NSCLC, but negatively or weak positively react to human small-cell lung cancer (SCLC), pulmonary pseudotumor and other epithelial tumors. In soft agar assay, the colony formation efficiency in NJ001 groups decreased in a dose-dependent manner. For the concentration of 100 μg/ml, 200 μg/ml and 400 μg/ml, the inhibition ratio of colony formation was 23.4%, 62.5% and 100% respectively. Meanwhile, NJ001 caused significant reduction in tumor volume and tumor weight compared to control mice in lung cancer xenograft model. The tumor growth inhibition ratio in 200 μg, 400 μg and 800 μg NJ001 groups was 10.44%, 37.29% and 44.04%, respectively. NJ001 also led to obvious cytomorphological changes and induced the apoptosis of human lung adenocarcinoma cell line SPCA1 significantly. The newly developed NJ001 selectively reacted to NSCLC and exhibited anti-tumor activity both in vitro and in vivo. SP70 is of great value concerning immunodiagnostics and immunotherapy for NSCLC and holds promise for further research regarding the mechanism underlying tumor progression of NSCLC.

Sessions:
Poster Presentations

Time:

Title: Targeted anticancer drug discovery based on natural product derivitives

Ao Zhang
Chinese Academy of Sciences, China

Biography

Professor Zhang received the Ph.D. diploma in 2000, and did Postdoctoral research at Georgetown University and Harvard Medical School during 2002-2004. He was promoted to Instructor of Harvard Medical School in 2004 and received the Hundred Talent Project award from the Chinese Academy of Sciences, and became the Professor of Medicinal Chemistry at Shanghai Institute of Materia Medica (SIMM). In 2011, he was awarded the Distinguished Young Investigator Award from Chinese Natural Science Foundation. He has authored or co-authored over 110 publications and 40 patents. Several drug candidates from his research group are now under clinical or preclinical studies.

Abstract

Anti-malaria natural product artemisinin (Qinghaosu) has been repositioned for the development of novel antitumor agents due to its unique structure and safety profile. Nevertheless, compared to the great success in the development of anti-malarial drugs, the majority of reported artemisinin analogues (artemalogues) only displayed limited in vitro and in vivo anticancer potency. In addition, the precise anticancer mechanism of these artemalogues) are also poorly understood. Therefore, chemical modification on artemisinin is highly needed both for the development of more potent anticancer artemalogues and for the understanding of the mode of actions. Most of the reported structural modifications focuse on the C10-carbonyl function with the aim to enhance the pharmacokinnetical properties. To generate structurally more diverse artemalogues, we conducted an alternative medicinal chemistry campaign by constructing various heterocyclic functionalities at the less explored sites including C-6 and -9 positions through 1,3-dipolar cycloaddition or click reaction, thus affording a series of structurally novel artemalogues. Several compounds demonstrated superior in vitro antiproliferative effects against cancer cell lines with IC50 values in nanomolar ranges. We further investigated the effects of artemisinin and three potent artemalogues on protein expression in whole A549 cells by using mass spectrometry-based global chemical proteomics approach, and systematically identified dozens of significantly up- and down-regulated proteins through quantitative proteomic analysis, some of which are involved in essential biological processes. These findings will shed light on the understanding of anticancer action mechanism of artemalogues.

Time:

Title: Assessment of selected transcription factors and neoplastic markers in stainless steel welders

Tadeusz Halatek
Nofer Institute of Occupational Medicine, Poland

Biography

Tadeusz Hałatek studied at the Faculty of Pharmacy, Medical University of Lodz. In 1991 received Ph.D in pharmacy Medical University of Lodz,. In 1974 started working in the Department of Biochemistry, Nofer Institute of Occupational Medicine (NIOM) in Łódź as an assistant and then assistant professor in the Department of Toxicology and Carcinogenesis, NIOM (1991-2011). Since 2011 Professor in the Department of Biological and Environmental Monitoring, NIOM. The main scientific interest of his work was identification of early biomarkers of critical effects of metals in occupational environmental for assessing the associated health risk. In studies on the respiratory biomarkers, he collaborated with the Catholic University of Louvain, Brussels, Belgium. in 1994-1995.

Abstract

The exposure to toxic fumes generated during welding of stainless steel (SS) is toxic due to chromium content and the reduction of Cr (VI) to Cr (V), a cascade of reactions involving the production of reactive oxygen specis (ROS). Generation of ROS may be induced also by nickel, leading to cytotoxicity and apoptosis. The study focused on two transcription factors: NF-kappa-B (nuclear factor of kappa light polypeptide gene enhancer in B-cells 1) and AP-1 (activator protein 1). NF-kappa-B is encoded by one gene: NFKB1. AP-1 is a protein complex that consists mainly of two protooncogenic families: Jun (c-Jun, JunB, JunD) and Fos (c-Fos, FosB, Fra-1, Fra-2), encoded by eight genes: JUN, JUNB, JUND, FOS, FOSB, FOSL1 and FOSL2. The study of SS welders was undertaken to observe the relationship between NF-kappa-B and AP-1 and some plasma neoplastic markers (carcinoembryonic antigen (CEA), cytokeratin fragment antigen 21-1 (CYFRA 21-1 and prostate specific antigen (PSA)). Study participants included controls (n=50) and exposed SS welders (n=50) from production departments, exposed to the welding fumes at 0.12-3.50 mg/m3 (inhalable fraction) and 0.12-1.65 mg/m3 (respirable fraction). Total concentration of metals (g/m3) was Fe 264.0, Mn 42.2, Cr 83.3 and Ni 40.4. mRNA expression for JUNB, JUND, FOS, FOSB and FOSL2 was significantly increased in the exposed welders (as compared to controls). No significant changes were observed for NFKB1, JUN and FOSL1. Expression of majority of mRNA transcripts was inversely correlated with serum cyfra21 levels in controls but not in the exposed welders. No correlation between mRNA expression of AP-1/ NF-kappa-B and CYFRA 21-1 in welders may indicate disrupted cytoprotective mechanisms associated with AP-1/ NF-kappa-B, specifically with respect to lung cancer development.

Time:

Title: The clinical usefulness of anti-Mullerian hormone evaluation in breast cancer patients who are taking Tamoxifen

Cheol Min Kang
University of Ulsan, Republic of Korea

Biography

Abstract

In premenopausal, hormone receptor (+) breast cancer patients, anti-hormone therapy is very important therapy for preventing cancer recurrence. It is recommended for the patients, after taking Tamoxifen for five years, to either continue with Tamoxifen or change to the aromatase inhibiter, depending on their menopausal status. The important problem for clinicians is that a woman has no menses does not mean the women is no longer producing estrogen, which could compromise the effectiveness of the aromatase inhibitor. So it is needed to know whether the woman was really in menopausal state or not. The elevated serum follicle stimulating hormone (FSH) level may be helpful in confirming menopause. Mean serum FSH level increases with age and be significantly higher in the 40 to 50 years, the period of initiation of menopause. However, it is known that a woman administered with Tamoxifen usually has a tendency of low serum FSH level. Serum anti-Mullerian hormone (AMH) level may be more accurate indicator of menopausal status than serum FSH level in perimenopausal, hormone receptor(+) breast cancer patients who were treated with Tamoxifen for 5 years and were considered additional anti-hormone therapy. We evaluated the perimenopausal women who were visited the survivor clinic in breast cancer department of Asan Medical Center between December 2014 and January 2016. All the patients had a surgery and were recommended to take Tamoxifen 20mg. Totally 46 perimenopausal women were enrolled and analyzed. The relationship between the presence of menopause and serum FSH and AMH levels was assessed using Pearson Chi-square test. We compared the relationship of the patient’s biological menopause and laboratory menopause (serum FSH>30mIU/mL, serum AMH<0.08ng/mL). Statistically, menopause compared to FSH levels has no significant relationship. (p value: 0.157) but menopause compared the AMH levels has significant relationship. (p value: 0.017) We concluded anti-Mullerian hormone can beaaccurate predictor of menopause than follicular stimulating hormone in perimenopausal, hormone-receptor (+) breast cancer patients who were treated with Tamoxifen.

Time:

Title: Novel approaches based on immune checkpoints for cancer immunotherapy

Jorge Augusto Borin Scutti
MD Anderson Cancer Center, USA

Biography

Dr. Jorge Augusto Borin Scutti is currently Research Scientist of Immunotherapy Platform (Immunology Department) at the MD Anderson Cancer Center (Houston-Texas). As Research Scientist hisworks focuses onanalyzing the activity of innate and adaptive cell populations like T cells, B cells, tumor cells, Myeloid Derived Suppressor Cells (MDSC) and Natural Killer (NK) cells that are critical on immune response against cancer and then might regulate positively or negatively T-cell responses.Dr. Scutti earned his Master and PhD in Microbiology and Immunology Department at Federal University of São Paulo (UNIFESP) working on cancer vaccines and peptides derived proteins to stimulate immune system against melanoma. Postdoctoral at MD Anderson Cancer Center (MDACC) - Pediatrics Department, where he began evaluating pediatrics cancer - DIPG (Diffuse Intrinsic Glioma Pontine) its microenvironment, Natural killer cells and histone deacetylase inhibitors (iHDAC) as cancer immunotherapy tool. Experience in cancer immunology and immunotherapy in experimental studies and clinical research.

Abstract

Introduction: Cancer immunotherapy is one of the best therapies compared to traditional therapies that may cause potential toxicities such as chemotherapy and radiation. The potential use of immunotherapy is to restore the immune system of patients in attempt to stimulate it to reject and destroy cancer cells. With the recent approval of the monoclonal antibodies against CTLA-4 and PD-1 for the treatment of melanoma, renal carcinoma cancer and non-small cell lung have attracted wide interest for strategies that enhance T-cell-mediated response against cancer. A complex network of biological pathways governs interactions between the immune system and cancer cells. The balance of signaling via co-inhibitory or co-stimulatory molecules expressed on T cells has demonstrated to be a powerful approach to intensify antitumor immune responses. This approach has been used effectively for the generation of a new class of anticancer therapies called checkpoint-blocking antibodies. Exploiting on the success of CTLA-4 blockade, agents that target a second co-inhibitory receptor, PD-1 (Programmed cell death protein 1), or its ligand, PD-L1, are in clinical development. Research: The presence of several inhibitory pathways that block T cell responses offers particular strategies for mobilizing the immune system to attack cancer cells.There are some strategies to modulate the microenvironment - targeting regulatory cells, blocking differentiation or recruitment, blocking immunosuppressive enzymes, regulatory cell depletion, re-programming immunosuppressive cells, modifying the chemokine and cytokine profile are some examples. The attractively of new strategies for immunotherapy is driven by immune response and microenvironment discovery.Usually, scientists have relied on conventional laboratory research tools to identify several biomarkers, for example, altered genes transcription factors changes in mRNA and protein expression. To put these cancer biomarkers in the context the researchers can use several strategies to find a good parameter to take care of patient and drug development.As more and more immunotherapies are made available, the overall goal will be to screen patients and determine which of the immunotherapies will be more effective for each cancer type and each patient, including the analysis of new immune cell population. Results: Currently there are several Clinical Trials across more than 20 different cancers including, melanoma, ovarian, prostate, breast, lung, gastric, kidney, bladder, cervical, anal, colorectal and pancreatic cancers, as well as in leukemia, lymphoma, sarcoma and glioblastoma. Inhibitory molecules like CTLA-4, PD-1, LAG-3, TIM-3, VISTA and BTLA besides co-stimulatories molecules such as ICOS, OX40 and 4-1BB are potent agents for combination therapy in order to improve antitumor responses.The analysis of tissue and blood samples from cancer patients is being conducted with new technologies as Flow Cytometry (FACS) and mass cytometry (Cytof). Here, we will share some strategies in order to pursuit molecules that could help us to better understand cancer immunotherapy responses. Conclusion: A harmonized struggle to assess the value biomarkers that address different aspects of the cancer-immunity cycle in T cell checkpoint blockade will allow us to integrate information on individual aspects of tumor-immune interaction.

Time:

Title: To perform chemotherapy or not, that is a question in elderly patients with pancreatic cancer

Ho Gak Kim
Catholic University of Daegu School of Medicine, S Korea

Biography

Professor Ho Gak Kim has completed his M.D. at the age of 26 years from Kyungpook National University School of Medicine, Taegu, South Korea. He is the Chief of Physician at Catholic University of Daegu School of Medicine, Daegu, South Korea since 2013. He has published more than 100 papers in reputed journals and has been serving as a president of Korean Pancreatobiliary Association since 2014, and editorial board member of Clinical Endoscopy.

Abstract

Background/Aims: Pancreatic cancer is a disease seen predominantly in elderly patients. Chemotherapy (CTx), which is one of the standard treatments for locally advanced and metastatic pancreatic cancer, is considered therapeutic modality with high risk in elderly patients. This study investigated the outcome and tolerability of chemotherapy in elderly patients with pancreatic cancer. Methods: Between January 2010 to January 2016, 226 patients were diagnosed with pancreatic cancer. Among them, patients with over 70 years old were reviewed retrospectively and clinical parameters, survival rate from initial chemotherapy, and adverse events during chemotherapy were analyzed. Results: Among 226 patients, 84 patients (34.7%) were older than 70 years of age and gemcitabine-based chemotherapy was performed in 57 patients (CTx group) and 27 patients were not received chemotherapy (non-CTx group). The overall median survival of total elderly patients was 8.2 months and the median survival of each group was 10.3 months in CTx group and 3.7 months in non-CTx group (p = 0.042). The incidence of adverse events such as bone marrow suppression (neutropenia, thrombocytopenia and anemia) was not different between younger patients (< 70 years) and older patients. The independent negative prognostic factors associated with survival were lower Karnofsky performance status (≤80) and presence of distant metastasis. Conclusions: The survival benefit can be achieved through gemcitabine-based chemotherapy in elderly patients without frequent adverse event. Karnofsky performance status and distant metastasis are independent prognostic factors.

Time:

Title: Key gene pathways shared by multiple cancers: Functional genomics analysis using machine learning

Katie Gao
Centennial High School, USA

Biography

Katie Gao is a junior at Centennial High School in Ellicott City, MD. She has been conducting research internship with Prof. Yi Huang at UMBC. She has always been deeply involved in science and has collected a few accolades along the way, including finishing top 20 at the 2016 National Brain Bee Championship and qualifying for the 2016 National Chemistry Olympiad.

Abstract

Despite a wealth of literature on identifying gene signatures for individual types of cancer, little has been reported regarding the comparison of gene signatures across multiple cancers to identify potential common-cancer gene signatures. We hypothesize that multiple cancers can be triggered and/or regulated by similar gene pathways; additionally, we aim to identify promising gene signatures to aid the diagnostic screening of multiple cancers in a more timely and accurate fashion. The advent of the big data era for cancer functional genomics, powered by high-throughput technologies (such as microarrays) and machine learning, has opened up a new path to study these hypotheses. The goals of this study are: (1) to collect gene signatures for individual cancers and evaluate their predictive ability across multiple cancers; (2) to identify potential common gene pathways for multiple cancers; and (3) to construct a meta-classifier to predict multiple cancers. We utilized 14 publicly available microarray gene expression datasets for a variety of cancers from the NCBI-GEO database. Our machine learning analysis indicated high predictive accuracy among the gene signatures identified from the datasets of breast, mammary gland, endometrial, and female non-smoker lung cancers; the results suggest a promising underlying genetic commonality. We will also present enrichment analysis of the predictive genes and demonstrate the relationship among gene pathways across multiple cancers. Our computational algorithm for the meta-classifier of multiple cancers will be shown at the end.

Time:

Title: Role of psychological support in cancer care and treatment

Shriya Shripad Ambhaikar
Dali Medical University, China

Biography

Ms. Shriya Shripad Ambhaikar is Studying in 3rd year, Clinical Medicine, M.B.B.S. in Dali Medical University, Dali, Yunnan Province, China. She has cleared her previous exams in honors. She has received a prize for her performance in International Day Ceremony of Dali University on April 2015. She has given a seminar on Addison's disease during clinical medicine seminar in china and received a Best Presentation Award on October 31st 2015. She has also received a best performance award in international competition in 2015. She has also received an award of Excellence on 6th January 2016 for her best performance. She has also published a research paper 'Role of Information and communication technologies in medical science and research' in an International Conference on Advances in Information technology and Management 2016 and her paper also published in International Journal IJCA. She is also doing her research in diabetes over artificial pancreas and preparing data bases on the same. She has a great interest in the field of research. She wants to contribute her study and knowledge for the better healthcare of society.

Abstract

Cancer has a major impact on society across the world. It is among the leading causes of death worldwide. This examines the evidence for psychological factors and therapies that affects the patient's journey from diagnosis through treatment and long-term survivorship or end of life. Every disease is psychosomatic. Psychological therapies help to increase patient's quality of life, boost their immune system and help them live longer. Implementation of this study may decrease the number of deaths of cancer causing patients. Evidence is convincing that emotional distress, depression, anxiety, uncertainty, hopelessness and negative thoughts unite and interact with pain. This unrelieved pain can increase the desire for hastened death. A variety of psychological therapies and processes can reduce pain severity and interference with function, as indicated in multiple meta-analysis and high quality randomized controlled trials. The effective methods and therapies include healing, yoga, meditation, breathing techniques and one of the most powerful Sudarshan Kriya which was introduced by Sri Sri Ravishankar ji who is an Indian. His years of meditation gave birth to this process which significantly reduces stress, depression, anxiety, pain, and increases well-being both mentally and physically. Experimental work performed on various patients suffering from cancer and this process helped them to develop positive energy, will power and self Confidence to fight with the physiological treatments like radiation, chemotherapy, surgery and the patient wins in the battle of life and death and survives. This introduces the modern medical science with ancient Indian healing and Sudarshan Kriya. “Approach of psychology over physiology" and the results were very positive. Research also demonstrates that the effects of Sudarshan Kriya reach all the way down to the molecular level, to our DNA. Exercise study have evaluated outcome. This showed promising results like better diagnosis, responds well to treatment, recovery rate got increased, high and positive energy level, enjoying better state of health. Study has done in India and China. The survey was taken from hospitals and organizations in order to know about the psychological support provided till date for the cancer patients. This study may bring the awareness among doctors and patients for the importance of psychological support in cancer in present time. Evaluation of methods has been described and the data set is prepared for the same. There are also few case studies discussed which shows the positive results of these therapies. Multidisciplinary teams are essential in oncology settings to integrate analgesic care, expertise in psychological support, therapies in standard care for symptom management, better effect of treatment as well as exact diagnosis including pain relief.

Sessions:
Contemporary Issues in Cancer & Structural Biology and Biomarkers

Time:

Title: Targeting cancer stem cells in urothelial cancer enhances chemotherapeutic response

Mohammad Obaidul Hoque
Johns Hopkins University, USA

Biography

Dr. Hoque is an Associate Professor of Otolaryngology-Head & Neck Surgery, Urology and Oncology at Johns Hopkins University School of Medicine. His major research interests includes: a) To understand molecular biologic basis of head and neck, lung and genitourinary cancer b) To develop and validate genetic and epigenetic approach for early cancer diagnosis, cancer risk assessment and cancer prognosis and c) To identify molecular alterations due to environmental exposures such as active smoking, passive smoking and arsenic. He has published over 95 papers in reputed journals and has been serving as an editor and/or editorial board member of several bio-medical journals.

Abstract

A large body of evidence indicates that cancer stem cells (CSCs) is the driving force of tumorigenesis, metastases and treatment resistance. However, the underlying mechanisms responsible for the urothelial CSC traits remain elusive. Here, we show that COX2/PGE2 and YAP1 signaling pathways are required to accelerate SOX2 that acts not only as a critical oncogene linked with malignant stemness properties, but also as a master regulator to govern and maintain urothelial CSCs. Moreover, we identify CD133+/CD24+ as a potent marker to enrich SOX2-expressing CSCs. Mechanistically, COX2/PGE2 signaling induces promoter methylation of let-7 host gene via promoting DNA methyltransferases, resulting in downregulated let-7 expression and subsequent SOX2 expression. YAP1 also activates COX2/PGE2 signaling-independent of SOX2 expression, and these signaling mutually compensate via negative feedback mechanism of SOX2, indicating that dual blockade of these signaling is indispensable to eradicate urothelial CSCs. Combined treatment with COX2 and YAP1 inhibitors elicits long-lasting therapeutic response by subverting CSCs expansion following chemotherapy or EGFR inhibitor for basal type urothelial carcinoma (UC) cells. Thus, our findings provide a rationale to concurrently target these pathways as an effective therapeutic strategy.

Time:

Title: Andrographolide inhibits angiogenesis and induces tumor suppressor gene RASSF1A expression in colon cancer cells

Aditi Banerjee
University of Maryland School of Medicine, USA

Biography

Aditi Banerjee received her Ph.D. from the University of Kalyani, India, in Zoology. She have a track record of driving advanced research by using a natural or synthetic compound to treat for different types of cancer and have extensive experience in cell biology with a focus on developing biomarkers for preclinical and clinical research against gastric ulcer, rheumatoid arthritis, breast cancer. Her early publications directly addressed in the area of basic and translational inflammatory diseases such as rheumatoid arthritis and gastric ulcer. At present, she is interested in the molecular mechanisms underlying the anticancer properties of phytochemicals andrographolide, labdane diterpenoid. Her current research is probing the effect of andrographolide on growth inhibiting, survival and apoptosis signal transduction pathway in colon cancer cells. In 2016, she joined the Department of Pediatrics, Division of Gastroenterology, and University of Maryland School of Medicine as an Assistant Professor.

Abstract

The diterpenoid lactone andrographolide (AGP) isolated from a plant, Andrographis paniculata, is known to possess multiple pharmacological activities. It has also been demonstrated to possess anticancer activity in vitro and in vivo. Frequent epigenetic silencing of tumor suppressor genes plays a pivotal role in the development of cancer and several recent reports suggest that suppression of RASSF1A is associated with the advanced grade and stage of many cancers including colon cancer. The goal of the present study was to investigate AGP anticancer activity due to the induction of tumor suppressor genes. T84, Colo 205 and HCT-116 colon cancer cells were treated with AGP IC50 and evaluated for expression of tumor suppressor genes by QRT-PCR and immunoblot. Inhibition studies were performed by transfection with gene specific siRNA prior to AGP treatment. AGP induced significantly higher expression of RASSF1A, PTEN, and CDKN2A in colon cancer cells whereas all other tumor suppressor genes tested were either unchanged or suppressed. Similar expression of RASSF1A was also observed in gastric, breast, lung, and prostate cancer cells. Whereas AGP treatment typically down-regulates cyclinD1, transfection of colon cancer cells with RASSF1A specific siRNA resulted in a loss of cyclin D1 suppression. RASSF1A is regulated through the epigenetic methylation of its promoter by DMNT activity which itself is activated by phosphorylated akt. Since Akt is a crucial element of the angiogenesis pathway, we examined the inhibition of this pathway by AGP on T84 and COLO 205 cells. AGP inhibited the transcriptional level of VEGF165 in both cell lines as well as vascular epithelial growth factor receptor 1 (VEGFR1) and VEGFR2. Additionally, downstream events including Akt activation and FoxM1 expression were significantly suppressed by AGP. FoxM1 is known to transactivate PTTG1, a major cause of colon cancer cell metastasis. Consistent with FoxM1 suppression, AGP also decreased transcriptional levels of PTTG1. Furthermore, we elucidated the AGP-dependent up regulation of anti-angiogenic molecule TSP-2, is a potent endogenous inhibitor of angiogenesis. These results demonstrate that AGP is a potent inducer of tumor suppressor genes, most notably RASSF1A and that RASSF1A is largely responsible for the cell cycle arrest induced by AGP treatment. These data also demonstrate the anti-angiogenic activity of AGP which may, through suppression of Akt activation, contribute to the up-regulation of RASSF1A.

Time:

Title: Growth, migration, and stress: Filling in the “gap”

Shoshanna N. Zucker
D'Youville College, USA

Biography

Shoshanna N. Zucker received her PhD in Molecular Pharmacology at Albert Einstein College of Medicine in the laboratory of Dr. Susan B. Horwitz who is well known for the discovery of the mechanism of action of taxol. Dr. Zucker did her postdoctoral work at the University at Buffalo where she focused on gap junctions in cancer. She was a recipient of an NIH NRSA fellowship. She specialized in melanoma research at Roswell Park Cancer Institute where she was a first author of several papers including a Molecular Cell study of oxidative stress in melanoma. In 2013, Dr. Zucker became an Assistant Professor at the D’Youville School of Pharmacy. Dr. Zucker established her independent research in the area of novel therapeutic approaches to cancer therapy utilizing oxidative stress-inducing mechanisms. She supervises many students and continues active collaborations with the University at Buffalo and Roswell Park Cancer Institute.

Abstract

Gap junctions promote intercellular communication that mediate the passage of molecules up to 1 kDa between cells. These molecules have been demonstrated to either inhibit or promote cell growth, thus defining gap junctions as either tumor suppressors or promoters of growth and metastasis. Although various defining molecular and clinical studies have been reported, there has been limited data to explain these seemingly conflicting results. In this report, the mechanism for how different connexins selectively promote growth through redistribution of cAMP is elaborated. In addition, the selective roles of gap junctions in migration which can affect metastasis is expanded and the key molecular molecules are defined including the mechanism for promotion of the epithelial to mesenchymal transition (EMT) and metastasis. Another role for gapjunctions is to transfer molecules that promote oxidative stress and apoptosis. This occurs by a mechanism known as the bystander effect by which stress applied directly to cells can affect adjacent and distal cells through gap junction communication. This can affect cancer therapy and identify novel ways to target cancer cells with limited side effects. We propose a novel therapeutic approach which has been demonstrated to decrease tumor volume in mice and may have clinical potential.

Time:

Title: The cancer stem cells generate the components for the constitution of the supporting tissues in cancer

Xianming Mo
West China Hospital, Sichuan University, China

Biography

Xianming Mo, M.D. is the Professor, Director, Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University. He identified a mechanism how the virus protein v-Myb is involved in the development of leukemia and how Akt pathway is involved in lung carcinomas. He did pioneering work on the cancer stem cells in periphery blood of patients with gastric carcinoma and evaluated the features of the circulating gastric cancer stem cells from patients. He also developed the methods to enrich the cancer stem cells from tumor masses removed from patients with gastric, colon rectal and lung carcinomas for further analysis. Now one of his works focuses on the biology of the cancer stem cells in human patients. He serves as director of Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University in Chengdu, China.

Abstract

The supporting tissues, including blood vessels, connection tissues and nerve tissues, are indispensablefor all the steps,such as tumorigenesis, growth, progression and metastasis,of cancer development in human. The extracellular matrix applies essential roles in cancer progress and metastasis. The nervous system acts as a crucial part of cancer microenvironment. Infiltration of nerve fibers into cancer microenvironment plays an important active role in cancer progression. The stimulation of both cancer growth and metastasis by members of nervous system such as neurons and glial cells has been demonstrated. The growth of cancers depends on the formation of blood vessels that provide the supply of nutrients and oxygen. The angiogenesis and vasculogenesis are essential during cancer progression. Previous data show that the glioblastoma stem cells are able to give rise to vascular cells to constitute the functional vessels in tumor tissues. However, which kinds of vascular cells generated from glioblastoma stem cells are largely debated. In addition, there are few evidences to show that the stem cells from other kinds of tumors including carcinoma produce vascular cells to constitute the functional blood vessels in tumor tissues. Therefore, how the components of supporting tissues originate and how the supporting tissues constitute in cancer need to be addressed. Here, we found that a fraction of cancer stem cells (CSCs) derived from patients with gastric carcinoma and colorectal carcinoma are capable to give rise to neurons that are involved in tumor neurogenesis and tumor growth. A single cancer stem cell is able to generate neurons including sympathetic and parasympathetic cells to take part in the nervous system in cancer tissues. Knocking down the neural generating capabilities of the human CSCs inhibited the growth of tumors in the mouse models. We also identified that cancer stem cells of human colorectal carcinomas (CoCSCs) give rise to vascular endothelial cells and compose the vasculatures in cancer tissues. CoCSC derivedendothelial cell incorporated blood vessels were functional. In addition, we identified that theextracellular matrix partially originated from cancer cells. Our data show that many components of supporting tissues originate from the cancer itself and provide an insight to understand how the cancer constitutes when the cancer occurs and progress.

Time:

Title: Restoration of Ikaros tumor suppressor function as a novel therapeutic approach for high-risk pediatric acute lymphoblastic leukemia

Sinisa Dovat
Pennsylvania State University College of Medicine, USA

Biography

Dr. Dovat completed his clinical training in Pediatrics at Pennsylvania State University, and in Pediatric Hematology/Oncology at UCLA-Children’s Hospital. He received his research training at Cornell University Graduate School of Medical Sciences and at Howard Hughes Medical Institute at UCLA. As an independent investigator at the University of Wisconsin, Dr. Dovat focused his work on the regulation of the tumor suppression in childhood leukemia. Dr. Dovat is the recipient of The Young Investigator Award by The American Society of Pediatric Hematology/Oncology and has been included in the Best Doctors in America list. Since September 2010, Dr. Dovat has served as the Four Diamond Endowed Chair and Director of Translational Research and Developmental Therapeutics in Pediatric Hematology/Oncology at Pennsylvania State University College of Medicine, Hershey, PA. Dr. Dovat’s research interests include epigenomic regulation and transcriptional control of cellular immortalization and senescence in leukemia and experimental therapy of malignant diseases.

Abstract

B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood malignancy. High-risk B-ALL remains a therapeutic challenge. Relapse occurs in 20% of B-ALL cases and the overall survival ofrelapsed B-ALL is only 50%. This survival rate has remained unchanged over the last 40 years. Thus, there is an urgent need to understand the pathogenesis of high-risk B-ALL and to develop targeted treatment for this disease. Clinical studies using next-generation sequencing showed that the chance for relapse in B-ALL is increased 12-fold when there is deletion/mutation of one copy of the IKZF1 gene that encodes the Ikaros tumor suppressor protein. Here, we present recent advances in understanding the tumor suppressor function of Ikaros, and the development of targeted therapy that aims to restore Ikaros activity as tumor suppressor. Ikaros is a zinc finger DNA binding protein, that binds to the upstream regulatory elements of its target genes and regulates their transcription. DNA-binding analysis, along with functional studies, showed that Ikarossuppresses leukemia by repressing transcription of genes that are essential for cell cycle progression and for the PI3K signaling pathway. Our results also demonstrated that Ikaros function in B-ALL is impaired by Casein Kinase II (CK2), a pro-oncogenic kinase that directly phosphorylates Ikaros, resulting in the loss of Ikaros activity as a transcriptional regulator. In B-ALL, the ability of Ikaros to control cell cycle progression and the PI3K pathway is impaired by CK2, which is overexpressed in leukemia. Inhibition of CK2 with a novel, specific inhibitor, CX-4945, restoresIkaros function as a regulator of cell cycle progression and PI3K and results in a strong anti-leukemia effect. The therapeutic efficacy of CK2 inhibition and its ability to restore Ikaros tumor suppressor function have been demonstrated in vivo, in preclinical models of high-risk B-ALL. These include primary xenografts derived from patients with high-risk B-ALL, including B-ALL with deletion of one Ikaros allele. In conclusion, this is the first demonstration that Ikaros tumor suppressor function can be reactivated, even in cases of high-risk B-ALL with deletion of a single Ikaros allele. These results present a novel treatment mechanism for high-risk B-ALL – restoration of Ikaros tumor suppressor activity – and provide a mechanistic rationale for the use of CK2 inhibitor for treatment of B-ALL.

Time:

Title: Survivin governs mitochondrial health by regulating the availability of phosphatidylethanolamine, PE

Sally Wheatley
University of Nottingham, UK

Biography

Sally Wheatley is originally from Scotland, Sally studied Zoology (Bsc hons) at St. Andrews University, before going to University College London where she studied (PhD) cell division cycle mutants in the fission yeast, S. pombe. After several post-doctoral positions, in France, the US and Edinburgh, she was awarded a Cancer Research UK Senior Fellowship and started her independent lab at the University of Sussex (2003-2009), where she focused her work primarily on the mitotic roles of survivin. Since 2009 she has been an Assistant Professor at the University of Nottingham where she teaches Biochemistry, and continues her research into the multiple roles and signaling pathways that involve survivin, from mitochondrial health to tumour metastasis.

Abstract

Survivin is an essential protein with established roles in mitosis and the inhibition of cell death. It is overexpressed in all cancers, its abundance correlating with tumour resistance to irradiation (IR). In normal cells, survivin expression is confined to the G2 and M phases; however, it is also present during interphase in the nucleus, the cytosol and the mitochondria of cancer cells PE is a phospholipid with a small head-group that facilitates negative curvature of membranes, thereby increasing their accommodation of proteins; thus it is enriched in specific membranes, such as the mitochondrial cristae and the cytokinetic furrow. Here we report the remarkable discovery that mitochondrial survivin regulates PE biosynthesis. The data suggest that survivin can govern mitochondrial integrity and metabolism, cell division and resistance to IR by limiting PE availability. This novel molecular insight suggests that many of the apparently disparate roles of this “multitasking” protein may be fundamentally linked to membrane architecture, and offers a completely unexpected perspective on its contribution to cancer and other metabolic disorders.

Time:

Title: Identification and isolation of single mesenchymal stem cells

Chaker Adra
Chief Scientific Officer & Chief Technology Officer, ACIAM-BFSRI, USA

Biography

Chaker Adra is investigating health, disease, and pioneering the field of organ engineering and regenerative medicine. He is discovering the Laws of Physics & Chemistry as manifested in The Language of Genomes and Living Organisms. He contributed to the emergence of the field of stem cell biology & tissue engineering. He cloned, characterized the family of phosphoglycerate kinase (PGK) genes and pseudogenes. He identified the PGK-1 promoter which has proven to be a powerful and widely used promoter. He designed and constructed The PGK1-Neo Vector which is being used around the world for gene therapy, to engineer, from embryonic stem cells, transgenic and knockout animals to understand the causes and mechanisms of all human diseases and find cures. He cloned the pgk-2 gene, showing for the first time that gene duplication, by retroposition more than 100 million years ago, have been used as a mechanism for evolutionary diversification and that mammalian genomes are fluid creating new species. He identified chromosomal regions containing asthma and atopy susceptibility genes. He described functional polymorphisms in Interleukin-4, IL-13 and their receptors, thus making these molecules, with STAT 6, targets for therapeutic treatment of allergic patients and preventive strategies. He discovered several cancer and stem cell specific biomarkers. In a series of groundbreaking experiments, he discovered several universal gene families and biochemical and/or physiological pathways operating in bacteria, yeast, plants, animals and humans (PGK, D4GDI/RhoGDI2/ARHGDIB, RhoGDI3/ARHGDIG, RTEF-1, HTm4/CD20L/MS4A Gene Family, LAPTM5, SMARCAD1 Helicase Gene Family, and SMARCAD1, The Fingerprints Gene). Dr. Chaker Adra is a philanthropist and the inventor of 19 USA and International Patents.

Abstract

Mesenchymal stem cells have properties that make them amenable to therapeutic use. However, the acceptance of mesenchymal stem cells in clinical practice such as in the treatment of diabetes and autoimmune diseases, cardiovascular disease, cancer therapy, and repair of birth defects require standardized techniques for their specific isolation. To date, there are no conclusive marker (s) for the exclusive isolation of mesenchymal stem cells. Our aim was to identify markers differentially expressed between mesenchymal stem cell and non-stem cell mesenchymal cell cultures.Examination and comparison of the phenotypes of mesenchymal stem cell and non-stem cell mesenchymal cell cultures revealed three differentially expressed markers - CD24, CD108 and CD40.We indicate the importance of establishing differential marker expression between mesenchymal stem cells and non-stem cell mesenchymal cells in order to determine stem cell specific markers, isolate and define Mesenchymal Stem Cells.

Time:

Title: Biomarker-driven therapeutic approaches for recurrent/metastatic salivary gland carcinomas

Renata Ferrarotto
University of Texas MD Anderson Cancer Center, USA

Biography

Dr. Ferrarotto received her MD degree and completed her Clinical Residency and Fellowship in São Paulo (Brazil). During her Fellowship at MD Anderson Cancer Center (2012-2014), Dr. Ferrarotto led a translational research project investigating biomarkers that predict sensitivity to Polo-like kinase 1 (PLK1) inhibitors in non-small cell lung cancers. Currently, Dr. Ferrarotto is an Assistant Professor focused on translational and clinical research in the Department of Thoracic/Head and Neck Medical Oncology, with a particular focus on the rarer tumor subtypes. Dr. Ferrarotto’s work focuses on identifying predictive biomarkers that can be used to select the patients that will benefit the most from targeted therapy and immunotherapy.

Abstract

Salivary gland carcinoma comprises a variety of histologies with distinct clinical behavior. Given disease rarity, no standard of care systemic therapy exists for patients with recurrent/metastatic disease. We have recently reported that Notch1 mutations define a distinct subgroup of adenoid cystic carcinoma patients with very aggressive disease and potential responsiveness to Notch1 inhibitors. Androgen blockage in salivary duct carcinoma overexpressing androgen receptor and TRK inhibitors in EVT6-NTRK3 fused mammary analogue secretory carcinoma are also promising targeted therapy undergoing clinical investigation and will be discussed.

Sessions:
Cancer Immunology & Cancer Metastasis

Time:

Title: Synergistic effects of oncolytic virotherapy in a bortezomib resistant syngeneic mouse model of multiple myeloma is mediated via immune modulation

Chandini Thirukkumaran
University of Calgary, Canada

Biography

Dr. Chandini Thirukkumaran is a Research Associate Professor at the Tom Baker Cancer Centre, University of Calgary, Calgary, Alberta. She received her PhD in microbiology in 1994 from the University of Calgary. Following completion of a post doctoral fellowship in signal transduction at the University of Calgary she joined the Translational Research Laboratories at the Tom Baker Cancer Centre, Calgary as a Research Assistant Professor in 1999. Since then her work has focused on oncolytic viruses as treatment modality for cancer. Presently she is conducting research on multiple myeloma and breast cancer and the effects of oncolytic viruses on immune modulation when given in conjunction with “standard of care therapies” for these malignancies.

Abstract

Introduction:Multiple myeloma (MM) is a plasma cell neoplasm that is considered incurable. Despite the advent of new agents the majority of MM patients relapse secondary to therapy resistance.The potential of reovirus (RV) as a novel therapeutic agent for MM under in vitro, in vivo and ex vivo conditions has been demonstrated by us and a phase I clinical trial of MM with RV therapy has shown indications of efficacy. Utilizing the syngeneic transplantable Vk*MYC bortezomib (BTZ) resistant MM mouse model, we demonstrate that mice harbouring BTZ insensitive MM tumors significantly respond to RV+BTZ combined treatment better than monotherapy. Our data indicate that this RV+BTZ synergy is manifested via, direct oncolysis in conjunction with enhanced immune activation. Methods:C57BL/6 wt mice were divided into 2 groups and transplanted with Vk*MYC myeloma (Vk12598) and were treated as follows, (N=8): 1) vehicle control (VC), 2) live reovirus (LV), 3) dead reovirus (DV), 4) BTZ, 5) LV+BTZ, 6) DV+BTZ. Mice in group 1 were sacrificed after 4 days of treatment and their spleens and bone marrow (BM) were formalin fixed and paraffin embedded. These were assessed for CD138+ MM tumour as well as viral RNA and protein in the tumour microenvironment (TME) and a variety of immune correlates as well as apoptotic markers. Mice in group 2 were assessed for serum gamma globulins (M-spike)on a weekly basis and overall survival analysis was conducted. Results: Mice treated with RV+BTZ demonstrated highly significant (P<0.001) reductions in their M-spikes at 3 and 4 weeks post treatment and superior overall survival (P<0.001). Analysis of tumour viral delivery/replication and immune activation in the TME as early as 4 days post treatment initiation indicated significant (P<0.01) viral replication, caspase 3 activity, CD3+ and NK cell accumulation in the RV+BTZ treatment. Conclusions: Our data indicate that this RV+BTZ synergy is manifested by enhanced apoptosis, successful viral delivery via tumour associated endothelial and follicular dendritic cells and immune modulation. Since the progression of MM is associated with concomitant immune suppression and drug resistance, these results have significant implications for shaping future clinical trials.

Time:

Title: T cell exhaustion is reinforced by progressive De novo DNA methylation programming

Ben Youngblood
Jude Children's Research Hospital, USA

Biography

Dr. Benjamin Youngblood, an assistant-member of the Department of Immunology at St Jude Children’s Research Hospital, investigates epigenetic mechanisms that regulate the functional impairment of CD8 T cells during chronic viral infections and cancer.Ben received his bachelor of science in Biochemistry from Oregon State University in 2001 and went on to do his graduate training in Biochemistry studying enzyme specificity of DNA methyltransferases at the University of California Santa Barbara. He joined Professor Rafi Ahmed’s laboratory in 2007 for postdoctoral training focused on investigating epigenetic regulation of memory CD8 T cell differentiation. In 2014 he joined the faculty at St Jude Children’s Research Hospital.

Abstract

Antigen-specific CD8 T cells play a critical role in controlling chronic infections and cancer, but progressively lose their effector functions during prolonged antigen exposure.Repression of CD8 T cell effector functions, commonly referred to as T cell exhaustion, limits the ability of the immune system to purge the chronic pathogen from the host. It has recently become recognized that CD8 T cell exhaustion programs can be reinforced and heritably maintained. Therefore in order to develop and/or improve current therapeutic approaches that utilize host antigen-specific T cells to treat chronic infections or cancer a major challenge for the field is to identify mechanisms that stabilize T cell exhaustion. We have recently found that epigenetic modifications acquired in pathogen-specific CD8 T cells during prolonged antigen exposure reinforce T cell exhaustion. Using the LCMV model system of chronic viral infection we investigated the role of Dnmt3a mediated de novo DNA methylation in regulating CD8 T cell exhaustion. Strikingly, conditional deletion of Dnmt3a in activated CD8 T cells blocked the cells from becoming exhausted. Longitudinal analysis of whole-genome methylation programming of WT and Dnmt3a cKO CD8 T cells from chronically infected animals reveals progressive acquisition of Dnmt3a-dependent DNA methylation programs in genes, including interferon gamma, that are coupled to the progressive decline of effector functions. These results have significant implications for therapeutic strategies that utilize reactivation of host pathogen-specific CD8 T cells to control chronic viral infections or cancerand provide a nucleotide-resolution map of epigenetic programs progressively acquired during T cell exhaustion.

Time:

Title: Metarrestin effectively disassembles PNCs and inhibits metastasis

Sui Huang
Northwestern University, Feinberg School of Medicine, USA

Biography

Abstract

Metastasis is the leading cause of cancer mortality. However, the development of effective anti-cancer drugs able to specifically block metastasis has been hampered by the complexity and poor understanding of the cellular mechanisms that regulate this process. To identify small molecules that selectively target metastatic development, a large diverse chemical library was screened searching for compounds able to eliminate the perinucleolar compartment (PNC). The PNC is a subnuclear structure, whose formation positively correlates with the metastatic potential of cancer cells. PNC prevalence in several cancers inversely correlates with clinical outcome. Metarrestin, a compound obtained through medicinal chemistry optimization of a hit from the screen, disassembles PNCs in cancer cells at submicromolar concentrations and inhibits cancer cell migration and invasion in vitro. In vivo, metarrestin effectively inhibits metastatic growth in murine xenograft models of metastatic disease using human pancreatic, prostate, and breast cancer cells. At doses able to disassemble PNCs, metarrestin selectively disrupts nucleolar structure and inhibits Pol I transcription without affecting Pol II transcription or protein translation and without eliciting DNA damage-repair and apoptotic responses. Affinity purification using a biotin-conjugated analog of metarrestin identified eEF1A as a binding partner. Manipulation of EEF1A levels by overexpression significantly enhance PNCs. Metarrestin is a well-tolerated molecule with a desirable pharmacokinetic profile and a novel mode of action, representing a new therapeutic approach to the treatment of metastatic cancer.

Time:

Title: Pharmacological activation of p53 protein family affects proliferation and migration of cancer cells with TP53 gene mutations

Joanna Zawacka-Pankau
Karolinska Institutet, Sweden

Biography

Dr. Joanna Zawacka-Pankau is a Principle Investigatorat KarolinskaInstittuet. She has done her Ph.D. at University of Gdansk, Poland under supervision of Prof. Anna J. Podhajska. Her research focused on activation of p53 tumor suppressor by small molecules and photodynamic therapy in colon cancer. In 2005 she joined Prof. Galina Selivanova Lab from the Department of Microbiology, Tumor and Cell biology, KarolinskaInstitutet as a postdoctoral fellow to study the mechanism and outcome of activation of wild-type p53 by small molecules. Then, she was appointed Assistant Professor at the Department of Biotechnology, Intercollegiate Faculty of Biotechnology, Gdansk, Poland where she focused on exploring the mechanism of tumor suppression upon pharmacological activation of p53 family members in p53 deficient and mutant tumors. In 2012 she took up a position of Assistant Professor at the Department of Microbiology, Tumor and Cell Biology and in 2016 she joined the Department of Clinical Science, Intervention and Technology.

Abstract

In the majority of all human cancer cases, the cancer suppressor protein p53 is lost or mutated. p53 belongs to a family of proteins that includes p73 and p63. The latter two can be categorized into two main groups: TA isoforms, which, like p53, act as tumor suppressors; and ∆N isoforms, which act like oncogenes and affect the functions of p53, TAp63, and TAp73. TP53 mutations lead to gain of function, which promotes more metastatic and fatal disease that are extremely difficult to cure. As reconstitution of p53 suppresses established tumors in vivo, current targeted therapies focus on the activation of p53 but this strategy is still difficult to implement therapeutically. A promising strategy to overcome p53 deficiency and restore p53 pathway functioning is to manipulate the p53 family members, TAp63 and TAp73. In our on-going efforts we identified small moleculesthat restore the p53 pathway and inhibit proliferation of cancer cells in tumors with various TP53gene mutations. TAp73 has been identified as a factor that engages pro-apoptotic signaling and inhibits migration of metastatic cancer cells. We propose a hypothesis that targeting interactions of TAp73 with its inhibitors with simultaneous inhibition of synthetic sick factors to those inhibitors can provide a therapeutic advantage over currently developed strategies to target tumors with TP53 loss or mutations.

Time:

Title: The function of the progesterone induced blocking factor (PIBF) protein in allowing escape of cancer cells from immune surveillance and the role of progesterone receptor modulators in treating various cancers

Jerome H. Check
Cooper Medical School of Rowan University, USA

Biography

Jerome H. Check, M.D., Ph.D. has been a Professor of Obstetrics and Gynecology and Division Head of Reproductive Endocrinology and Infertility at Cooper Medical School of Rowan University (formerly known as University of Medicine and Dentistry of Robert Wood since 1989. He is also board certified in internal medicine and medical endocrinology and metabolism. He received his Ph.D. in reproductive biology in 1997 and his thesis was “The role of progesterone in promoting implantation and inhibiting spontaneous abortions may be through the stimulation of immunomodulatory proteins”. He has published over 750 publications in peer review journals involving obstetrics/gynecology, reproductive and medical endocrinology and infertility, internal medicine, and cancer research. Much of his present cancer research relates to his concept published in the journal Medical Hypothesis in 2011 entitled “A model for potential tumor immunotherapy based on the knowledge of immune mechanism responsible for spontaneous abortion.

Abstract

There is evidence that rapidly growing cancer cells, similar to rapidly growing trophoblast cells utilize a unique protein, not present in normal tissue, to help evade immune surveillance. This protein known as the progesterone induced blocking factor (PIBF) has been found to stabilize perforin granules in natural killer (NK) cells, thus abrogating their mechanism for cytolysis and help cause a shift of TH1 to TH2 cytokines. PIBF has been found to be overexpressed in biopsies of uterus, breast, stomach, and brain cancer and in several cancer cell lines including leukemia, glioblastoma multiforme, and adenocarcinoma of the ovary, cervix, and breast. The parent form of PIBF measures 90 kDa and is associated with centrosome on chromosome 13 in the vicinity of BRCA-1 and P53. Isoforms of PIBF are produced by alternative splicing and includes ones measuring 34 kDa, 57 kDa, 67 kDa. Progesterone has been found to up-regulate the 34 kDa splice variant of PIBF on human leukemia cell lines and the 57 kDa isoform in human glioblastoma cells lines. PIBF, though present intracellularly in both the rapidly growing trophoblast cells and cancer cells, one distinction between pregnancy vs. cancer is that serum PIBF rises abruptly after progesterone exposure (even when not pregnant) in the serum but not increased in the serum even in tumors that are positive for progesterone receptors or even BRCA-1 breast cancer, which by making a mutated ubiquitin is associated with diminished capacity to degradate the progesterone receptor. Adding the progesterone receptor modulator mifepristone to culture media causes down-regulation of the 34 isoforms in leukemia and glioblastoma multiforme cell lines. However, mifepristone fails to lower serum PIBF. There is evidence that suppressing the conversion of the 90 kDa nuclear parent form to the intracellular isoforms can provide significant palliative benefit to a large variety of metastatic human cancers including colon, renal cell carcinoma, small and non-small cell lung cancer, glioblastoma multiforme, breast cancer, transitional cell carcinoma of the renal/pelvis and thymic epithelial cell cancer. It is suggested, but not proven for sure, that the mechanism for causing improved longevity and quality of life by retarding tumor growth is by inhibiting the production of intracellular PIBF which allows natural killer cells (and possibly T-cells also) to attack the cancer cells. Measuring serum PIBF does not appear to be a worthwhile test to determine who would benefit from mifepristone treatment nor the knowledge of progesterone receptor status.

Time:

Title: Novel approaches based on immune checkpoints for cancer immunotherapy

Jorge Augusto Borin Scutti
MD Anderson Cancer Center, USA

Biography

Dr. Jorge Augusto Borin Scutti is currently Research Scientist of Immunotherapy Platform (Immunology Department) at the MD Anderson Cancer Center (Houston-Texas). As Research Scientist hisworks focuses onanalyzing the activity of innate and adaptive cell populations like T cells, B cells, tumor cells, Myeloid Derived Suppressor Cells (MDSC) and Natural Killer (NK) cells that are critical on immune response against cancer and then might regulate positively or negatively T-cell responses.Dr. Scutti earned his Master and PhD in Microbiology and Immunology Department at Federal University of São Paulo (UNIFESP) working on cancer vaccines and peptides derived proteins to stimulate immune system against melanoma. Postdoctoral at MD Anderson Cancer Center (MDACC) - Pediatrics Department, where he began evaluating pediatrics cancer - DIPG (Diffuse Intrinsic Glioma Pontine) its microenvironment, Natural killer cells and histone deacetylase inhibitors (iHDAC) as cancer immunotherapy tool. Experience in cancer immunology and immunotherapy in experimental studies and clinical research.

Abstract

Introduction: Cancer immunotherapy is one of the best therapies compared to traditional therapies that may cause potential toxicities such as chemotherapy and radiation. The potential use of immunotherapy is to restore the immune system of patients in attempt to stimulate it to reject and destroy cancer cells. With the recent approval of the monoclonal antibodies against CTLA-4 and PD-1 for the treatment of melanoma, renal carcinoma cancer and non-small cell lung have attracted wide interest for strategies that enhance T-cell-mediated response against cancer. A complex network of biological pathways governs interactions between the immune system and cancer cells. The balance of signaling via co-inhibitory or co-stimulatory molecules expressed on T cells has demonstrated to be a powerful approach to intensify antitumor immune responses. This approach has been used effectively for the generation of a new class of anticancer therapies called checkpoint-blocking antibodies. Exploiting on the success of CTLA-4 blockade, agents that target a second co-inhibitory receptor, PD-1 (Programmed cell death protein 1), or its ligand, PD-L1, are in clinical development. Research: The presence of several inhibitory pathways that block T cell responses offers particular strategies for mobilizing the immune system to attack cancer cells.There are some strategies to modulate the microenvironment - targeting regulatory cells, blocking differentiation or recruitment, blocking immunosuppressive enzymes, regulatory cell depletion, re-programming immunosuppressive cells, modifying the chemokine and cytokine profile are some examples. The attractively of new strategies for immunotherapy is driven by immune response and microenvironment discovery.Usually, scientists have relied on conventional laboratory research tools to identify several biomarkers, for example, altered genes transcription factors changes in mRNA and protein expression. To put these cancer biomarkers in the context the researchers can use several strategies to find a good parameter to take care of patient and drug development.As more and more immunotherapies are made available, the overall goal will be to screen patients and determine which of the immunotherapies will be more effective for each cancer type and each patient, including the analysis of new immune cell population. Results: Currently there are several Clinical Trials across more than 20 different cancers including, melanoma, ovarian, prostate, breast, lung, gastric, kidney, bladder, cervical, anal, colorectal and pancreatic cancers, as well as in leukemia, lymphoma, sarcoma and glioblastoma. Inhibitory molecules like CTLA-4, PD-1, LAG-3, TIM-3, VISTA and BTLA besides co-stimulatories molecules such as ICOS, OX40 and 4-1BB are potent agents for combination therapy in order to improve antitumor responses.The analysis of tissue and blood samples from cancer patients is being conducted with new technologies as Flow Cytometry (FACS) and mass cytometry (Cytof). Here, we will share some strategies in order to pursuit molecules that could help us to better understand cancer immunotherapy responses. Conclusion: A harmonized struggle to assess the value biomarkers that address different aspects of the cancer-immunity cycle in T cell checkpoint blockade will allow us to integrate information on individual aspects of tumor-immune interaction.

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Title: Body mass index as a prognostic feature in breast cancer

Hojouj Mohammad
SE "Dnipropetrovsk medical academy of Health Ministry of Ukraine", Ukraine

Biography

Mohammad Hojouj is an Assistant Professor, MD, MSo, Oncologist, Master of medicine, a member of The National Comprehensive Cancer Network NCCN, a member of the European Association of Physicians in Germany (NGO), member of the international conference, Speaker of the international conference in the United Arab Emirates 2015, a member of the Association of Arab doctors in Ukraine. Actual Member of the American Association of Clinical Oncology (ASCO). Has experience of more than 9 international clinical researches as Sub investigator. He gives great attention to the educational process, organization and conduction of clinical trials in oncology practice.

Abstract

BACKGROUND: Breast cancer is the most common cancer diagnosed among women in the world. Current information on the prognostic importance of body mass index (BMI) for patients withbreast cancer is based on a variety of equivocal reports. Few have data on BMI in relationship to systemictreatmenthas not been explored so far. The aim of this retrospective study is to evaluate the relation between patients’ Breast cancer to Obesity and the prognosis of treatment. Materials and Methods: The study included 130 patients with breast cancer between the ages of 30 and 77 (57,6 ± 1) years of age who were treated according to our clinic, department of oncology and medical radiology . Dnipropetrovsk medical academy at Municipal Institution "Dnipropetrovsk City Multi-field Clinical Hospital #4", Dnepropetrovsk state medical academyfrom 2005-2015. All patients were evaluated according to the following data: stage of the disease, age and BMI at the time of diagnosis, the size, histological typeand metastases. Tumor size was evaluated after measuring its maximal diameter and distributed in accordance with the International TNM-classification (7th edition, 2009). The histological type and degree of differentiation of the tumor was evaluated respectively by the National Standards of diagnostics and treatment of malignant neoplasms, reflecting the recommendations of leading international organizations. BMI is calculated by the formula: I = m×h2, where m - body weight (kg); h - height (m). According to these calculations the patients were divided in accordance with the WHO criteria into the following groups: those with a BMI <25 kg/m2 - normal or underweight; from 25 to 29.9 kg/m2 - overweight; > 30 kg/m2 - obese. The material for the histopathological study was obtained during surgery.We examined the relative risk of relapse and death with regard to the BMIcategories adjusting for eight factors known to be predictors of disease-freesurvival (DFS) and overall survival (OS): menopausal status, nodal status tumor size, vessel invasion, estrogen receptor (ER) status, progesterone receptorstatus, tumor grade and treatment regimens. Results: In this retrospective study, among 130 patients with breast cancer, 45% were identified with excess body weight, and 31% - of various obesity degree. Patients with a BMI <25 kg/m2 were significantly more diagnosed with stage 2 breast cancer triple negative. BMI> 30 kg/m2, 10% more often associated with metastatic RLN, which is anindirect sign of higher metastatic potentials. Patients with normal BMI had significantly longer overall survival (OS) and disease-free survival (DFS) than patients with intermediate or obese BMI in pairwise comparisons adjusted for other factors.We found a strong correlation betweenobesity and lymph node involvement These observationssuggest that obesity may potentiate the metastatic spread of breast tumors. Distant metastases were also foundmore often in obese patients in bone or visceral sites in patients <45 years of age at diagnosis. Conclusions: In conclusion, this retrospective investigation our patient demonstrates that BMI is an independent prognostic factor for OS in patients with breast cancer. We have supporting evidencethat obese BMI represents a poor risk feature for outcome, especially in pre-/premenopausal patients, most of whom receivedchemotherapy without hormonal therapy.

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Title: Enhancing the efficacy of T cell-based immunotherapies using miR-155 engineered tumor-specific CD8+ T cells

Yun Ji
National Cancer Institute, National Institutes of Health, USA

Biography

Dr. Yun Ji obtained her Ph.D. from Iowa State University in 2004. Following a postdoctoral fellowship at Georgetown University she joined the National Cancer Institute in 2007. In 2016 Dr. Ji was appointed as a Staff Scientist at the Experimental Transplantation and Immunology Branch in the National Cancer Institute.Dr. Ji is interested in the mechanism of CD8+ T cell development and differentiation. Her research focuses on the identification and characterization of key transcription factors, miRNAs, and epigenetic modulators essential for CD8+ T cell activation, differentiation, and function, with a goal of improving T cell-based immunotherapy against cancer.

Abstract

Lymphodepleting regimens are employed prior to adoptive immunotherapy to augment the antitumor efficacy of transferred T cells by removing endogenous homeostatic ‘cytokine sinks’. These conditioning modalities, however, are often associated with severe toxicities. We found that miR-155 enabled B16 melanoma-specific CD8+ T cells to mediate profound antitumor responses in lymphoreplete hosts that were not potentiated by immune-ablation. miR-155 enhanced T cell responsiveness to limited amounts of homeostatic γc cytokines by restraining the expression of the Akt inhibitor Ship1 and multiple negative regulators of Stat5, such as Socs1 and Ptpn2, resulting in delayed cellular contraction and sustained cytokine production. To translate these findings into new clinical trials, we tested whether the overexpression of miR-155 in human T cells would enhance the antitumor efficacy of CD19-specific chimeric antigen receptor (CD19-CAR) cells against systemic acute lymphoblastic leukemia xenografts. As a safety measure, the suicide gene, inducible caspase 9, was included in the miR-155 construct. We found that miR-155 also augmented the antitumor efficacy of T cells in this xenograft tumor model. Recapitulating our findings in mouse cells, human T lymphocytes overexpressing miR-155 showed increased Stat5 signaling and enhanced survival. Our results indicate that overexpression of miR-155 in tumor-specific T cells can be employed to increase the effectiveness of adoptive immunotherapies in a cell intrinsic manner without the need of life-threatening, lymphodepleting maneuvers.

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